A Pilot Trial to Explore the Link Between Immunological Changes, Efficacy, Safety, and Tolerability of Durvalumab (MEDI4736) Plus Tremelimumab in Chemotherapy-Naïve Men With Metastatic Castration-Resistant Prostate Cancer (CRPC)
Phase: PHASE2
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Malignant Neoplasm in the Bone, Prostate Adenocarcinoma, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2016-0769 
Protocol Title 
A pilot trial to explore the link between immunological changes, 
efficacy, safety and tolerability of durvalumab (MEDI4736) plus 
tremelimumab in chemotherapy-naive men with metastatic castration-
resistant prostate cancer (CRPC) 
Protocol Phase 
Pilot 
Protocol Version 
9 
Version Date 
07/28/2020 
 
Protocol PI 
Sumit K. Subudhi MD, PhD 
Department 
U.T. M. D. Anderson Cancer Center Department of Genitourinary 
Medical Oncology 1155 Pressler,  
Unit 1374 
Houston, Texas 77030 
Phone: (713) 792-2830 
Fax: (713) 745-1625 
Email: sksubudhi@mdanderson.org 
 
 
Sponsor and IND 
holder 
MD Anderson Cancer Center 
IND # 
130,932 
Investigational 
Drug 
Durvalumab (MEDI4736) and 
Tremelimumab 
Supporter 
AstraZeneca MedImmune 
Supporter Study 
Number 
ESR-15-11590 
 
Sponsor: M.D. Anderson Cancer Center IND Office 
Document Submitted 
PDOL Version # 
Header Date 
Status 
All documents 
v00 
02/27/2017 
Submission 
All documents 
v01 
03/20/2017 
CRC 
Protocol 
v02 
03/28/2017 
IRB Approved with Contingency 
All Documents 
v03 
04/13/2017 
IRB Approved 
Protocol 
V04 
04/20/2017 
Update of Protocol Title 
Protocol 
V05 
07/24/2017 
Update 
Protocol 
V06 
12/01/2017 
Update the Protocol 
Protocol 
V07 
01/11/2018 
Protocol Update 
Protocol 
V08 
02/14/2019 
Protocol Update 
Protocol  
V09 
07/28/2020 
Biosample analysis plus waivers 
 
 
 
 
 
 

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TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS ......................................................................................................... 2 
ABBREVIATIONS AND DEFINITION OF TERMS ............................................................ 3 
1.0 
INTRODUCTION ................................................................................................... 8 
2.0 
STUDY OBJECTIVE ........................................................................................... 24 
3.0 
STUDY DESIGN .................................................................................................. 24 
4.0 
PATIENT SELECTION, ENROLLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL .................................................... 25 
5.0 
INVESTIGATIONAL PRODUCT(S) .................................................................. 30 
6.0 
TREATMENT PLAN ........................................................................................... 30 
7.0 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) .................................................................................................. 37 
8.0 
STUDY PROCEDURES ....................................................................................... 39 
9.0 
DISEASE EVALUATION AND METHODS ...................................................... 52 
10.0 
ASSESSMENT OF SAFETY ............................................................................... 55 
11.0 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 85 
12.0 
STUDY MANAGEMENT .................................................................................... 89 
13.0 
LIST OF REFERENCES....................................................................................... 91 
APPENDIX 1. 
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW ................................... 100 
APPENDIX 2. 
DURVALUMAB DOSE CALCULATIONS ........................................ 105 
APPENDIX 3. DURVALUMAB DOSE VOLUME CALCULATIONS ........................... 106 
APPENDIX 4. 
TREMELIMUMAB DOSE CALCULATIONS .................................... 107 
APPENDIX 5. 
TREMELIMUMAB DOSE VOLUME CALCULATIONS .................. 108 

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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
 
Abbreviation 
special term 
or Explanation 
AChE 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion  of  patients  alive  and  progression  free  at 12 months 
from 
randomization 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-28day 
Area under the plasma drug concentration-time curve from time zero to Day 
28 post-dose 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
BICR 
Blinded Independent Central Review 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
CR 
Complete response 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
Ctrough,ss 
Trough concentration at steady state 

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Abbreviation 
special term 
or Explanation 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Duration of response 
EC 
Ethics Committee, synonymous to Institutional Review Board and 
Independent Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICOS 
Inducible COStimulator 
IFN 
Interferon 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product 
irAE 
Immune-related adverse event 

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Abbreviation 
special term 
or Explanation 
IRB 
Institutional Review Board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IV 
Intravenous 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Prometheus 
Partial response 
Electronic database 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 

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Abbreviation 
special term 
or Explanation 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SOC 
Standard of Care 
sPD-L1 
Soluble programmed cell death ligand 1 
T3 
Triiodothyronine 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 

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1.0 
INTRODUCTION 
 
Prostate cancer is the second leading cause of cancer death among men in the United States. The 
first-line treatment for advanced prostate cancer is androgen deprivation therapy (ADT), which 
initially results in tumor regression; however, the tumor eventually progresses, a clinical state 
known as castration-resistant prostate cancer (CRPC) to which most men eventually succumb. The 
taxane chemotherapies (docetaxel and cabazitaxel) and drugs targeting the androgen receptor (AR) 
signalling pathway (enzalutamide and abiraterone acetate) have been FDA-approved for the 
treatment of CRPC for their proven survival benefit in definitive Phase III clinical trials (2-7). 
Despite the clinical success of these agents that target the tumor epithelial cells, none of them 
induce durable responses. 
 
Approximately 80% of patients with advanced prostate cancer have metastatic disease that has 
spread to the bone. The interaction between the tumor and its microenvironment in the bone 
promotes plays a key role in metastatic growth of prostate cancer. The significance of the 
microenvironment has been confirmed by the clinical successes of the following drugs: 1) bone- 
homing radiopharmaceutical, radium-223 (Xofigo); and 2) the prostate cancer vaccine, sipuleucel- 
T (Provenge). Sipuleucel-T and radium-223 prolong survival in advanced prostate cancer without 
decreasing serum prostate-specific antigen (PSA). Agents that target primarily the tumor would be 
expected to decrease PSA; providing evidence that the above-described drugs target primarily the 
tumor microenvironment. Unfortunately, in most patients, radium-223 and sipuleucel-T only also 
prolong survival without providing durable responses. Therefore, there is an unmet need to find 
therapies that in addition to modulating the cancer epithelial cells and the tumor microenvironment, 
also induce durable clinical responses. 
 
1.1 
Disease Background 
 
Immune responses directed against tumors are one of the body’s natural defense against the growth 
and proliferation of cancer cells. However, over time and under pressure from immune attack, 
cancers develop strategies to evade immune-mediated killing allowing them to develop unchecked. 
One such mechanism involves upregulation of surface proteins that deliver inhibitory signals to 
cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such protein, and is upregulated 
in a broad range of cancers with a high frequency, with up to 88% expression in some tumor types. 
In a number of these cancers, including lung (Mu et al, 2011), renal (Thompson et al, 2005; 
Thompson et al, 2006; Krambeck et al, 2007), pancreatic (Nomi et al, 2007; Loos et al, 2008; 
Wang et al, 2010), ovarian cancer (Hamanishi et al, 2007), and hematologic malignancies 
(Andorsky et al, 2011; Brusa et al, 2013) tumor cell expression of PD-L1 is associated with reduced 
survival and an unfavorable prognosis. 
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumors to help evade detection and elimination by the 
host immune system tumor response. In the lymph nodes, PD-L1 on antigen-presenting cells binds 
to PD-1 or CD80 on activated T cells and delivers an inhibitory signal to the T cell (Keir et al, 
2008; Park et al, 2010). This results in reduced T-cell activation and fewer activated T cells in 
circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and 

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CD80 on activated T cells reaching the tumor. This delivers an inhibitory signal to those T cells, 
preventing them from killing target cancer cells and protecting the tumor from immune elimination 
(Zou and Chen, 2008). 
 
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. T cells play a critical role in antitumor immunity and their 
infiltration and activity have been linked to improved prognosis in a number of cancers (Pagès et al, 
2010; Nakano et al, 2001; Suzuki et al, 2011; Burt et al, 2011). Immune evasion, primarily through 
suppression of T-cell activity, is now recognized as one of the hallmarks of cancer. Such evasion 
can occur via a range of mechanisms including production of suppressive cytokines such as IL-10, 
secretion of chemokines and growth factors that recruit and sustain suppressive regulatory T cells 
(Tregs) and inflammatory macrophages, and expression of inhibitory surface molecules such as 
B7-H1. Tumor types characterized as being responsive to immunotherapy-based approaches include 
melanoma (Weber et al, 2012), renal cell carcinoma (RCC; McDermott, 2009), bladder cancer 
(Kresowik and Griffith, 2009), and malignant mesothelioma (Bograd et al, 2011). Inhibition of 
CTLA-4 signaling is a validated approach to cancer therapy, as shown by the approval in 2011 of 
ipilimumab for the treatment of metastatic melanoma based on statistically significant and 
clinically meaningful improvement in OS (Hodi et al, 2010; Robert et al, 2011). 
 
In general, tumor response rates to anti-CTLA-4 therapy are low (~10%). However, in patients 
who respond, the responses are generally durable, lasting several months even in patients with 
aggressive tumors such as refractory metastatic melanoma. Because these agents work through 
activation of the immune system and not by directly targeting the tumor, responses can occur late 
and some patients may have perceived progression of their disease in advance of developing 
disease stabilization or a tumor response. In some cases, early growth of pre-existing lesions or the 
appearance of new lesions may have been due to immune-cell infiltration into the tumor and not 
due to proliferation and extension of neoplastic cells, per se (Wolchok et al, 2009). Overall, 
although the impact on conventionally-defined PFS can be small, durable response or stable 
disease seen in a proportion of patients can lead to significant prolongation of OS. The melanoma 
data with ipilimumab clearly demonstrate that a small proportion of patients with an objective 
response had significant prolongation of OS, supporting the development of this class of agents in 
other tumors. Although Phase 2 and Phase 3 studies of tremelimumab in metastatic melanoma did 
not meet the primary endpoints of response rate and OS, respectively, the data suggest activity of 

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tremelimumab in melanoma (Kirkwood et al, 2010; Ribas et al, 2013). In a large Phase 3 
randomized study comparing tremelimumab with dacarbazine (DTIC)/temozolomide in patients 
with advanced melanoma, the reported median OS in the final analysis was 12.58 months for 
tremelimumab versus 10.71 months for DTIC/temozolomide (HR = 1.1416, p = 0.1272; Ribas et 
al, 2013). 
 
Targeting CTLA-4 with ipilimumab in Phase 1 and 2 CRPC trials demonstrated clinical activity 
(Hodi et al 2010; Schiller et al 2002; Wolchok et al 2013). However, in a phase 3 trial comparing 
ipilimumab to placebo following radiotherapy in patients with CRPC who received prior 
treatment with docetaxel, ipilimumab barely failed to improve overall survival (Hodi et al 2010). 
 
Post hoc analyses revealed that treatment with ipilimumab improved the median overall survival 
in CRPC patients with favorable laboratory values, but without visceral metastases (Hodi et al 
2010). Furthermore, studies of other immunotherapies (eg, sipuleucel-T, poxvirus-based vaccine 
[PROSTVAC]) for CRPC have demonstrated that the extent of tumor burden influences outcome 
(Mu et al 2011; Nakano et al 2001). Therefore, immunotherapies such as targeting immune 
checkpoints may be most beneficial in chemotherapy naïve CRPC patients without visceral 
metastases who are asymptomatic or minimally symptomatic. 
 
We investigated whether the lack of significant therapeutic efficacy with ipilimumab in prostate 
cancer may be attributed to the immune tumor microenvironment by comprehensively analyzing 
the immune profile in a number of malignancies, including prostate cancer, melanoma, RCC, and 
bladder cancer. Prostate cancer, unlike the other malignancies, has very few immune infiltrates and 
low tumor expression of PD-L1; therefore, it is a relatively non-immunogenic tumor. Interestingly, 
there is data from three clinical trials suggesting that higher tumor expression of PD- L1 correlates 
with an increased likelihood of responding to therapies targeting PD-1 or PD-L1 (Mu et al 2011). 
Thus, it is not surprising that in a phase 1 study targeting PD-1 (nivolumab), treatment was 
ineffective in patients with CRPC (0/17 responses) (Drake et al 2013). 
 
However, our observations demonstrate PD-L1 expression is an adaptive response to CTLA-4 
blockade and support the hypothesis that CTLA-4 plus PD-1 inhibition will be an effective strategy 
to induce anti-tumor responses in patients with CRPC. We recently observed that following 
treatment with 2 doses of ipilimumab there is a markedly significant increase in tumor-infiltrating 
lymphocytes (TILs) and enhanced PD-1 and PD-L1 expression within the prostate tumor 
microenvironment. This suggests that CTLA-4 blockade has the potential of making prostate 
cancer immunogenic, but also that resistance to CTLA-4 blockade may be attributed to the PD- 
1/PD-L1 signaling pathway. Thus, simultaneously targeting CTLA-4 and PD-L1, may overcome 
resistance to CTLA-4 blockade. Our group was the first confirm this hypothesis in preclinical 
studies (Iwai et al 2002). 

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1.1.1 
Immunotherapies 
 
It is increasingly understood that cancers are recognized by the immune system, and, under some 
circumstances, the immune system may control or even eliminate tumors (Dunn et al 2004). 
Studies in mouse models of transplantable tumors have demonstrated that manipulation of co- 
stimulatory or co-inhibitory signals can amplify T-cell responses against tumors (Dunn et al 2004). 
This amplification may be accomplished by blocking co-inhibitory molecules, such as cytotoxic 
T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death 1 (PD-1), from binding 
with their ligands, B7 or B7-H1 (programmed cell death ligand 1 [PD-L1]). 
 
1.1.2 
Durvalumab 
 
The non-clinical and clinical experience is fully described in the current version of the durvalumab 
Investigator’s Brochure (see PDOL Appendices). 
 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for 
use in the treatment of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) As 
durvalumab is an engineered mAb, it does not induce antibody-dependent cellular cytotoxicity or 
complement-dependent cytotoxicity. The proposed mechanism of action for durvalumab is 
interference of the interaction of PD-L1. 
 
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some types of 
cancers. In a number of these cancers, including lung, the expression of PD-L1 is associated with 
reduced survival and an unfavorable prognosis. In lung cancer, only 12% of patients with tumors 
expressing PD-L1 survived for more than 3 years, compared with 20% of patients with tumors 
lacking PD-L1 (Mu et al 2011). Based on these findings, an anti-PD-L1 antibody could be used 
therapeutically to enhance anti-tumor immune responses in patients with cancer. Results of several 
non-clinical studies using mouse tumormodels support this hypothesis, where antibodies directed 
against PD-L1 or its receptor PD-1 showed anti-tumor activity (Hirano et al 2005, Iwai et al 2002, 
Okudaira et al 2009, Zhang et al 2008). 
 
Durvalumab has been given to humans as part of ongoing studies as a single drug or in combination 
with other drugs As of the DCO dates (15Apr2015 to 12Jul2015, durvalumab IB version 8.0), a 
total of 1,883 subjects have been enrolled and treated in 30 ongoing durvalumab clinical studies, 
including 20 sponsored and 10 collaborative studies. Of the 1,883 subjects, 1,279 received 
durvalumab monotherapy, 440 received durvalumab in combination with tremelimumab or other 
anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 150 have been treated 
with blinded investigational product. No studies have been completed or terminated prematurely 
due to toxicity. 
As of 09Feb2015, PK data were available for 378 subjects in the dose-escalation and dose- 
expansion phases of Study CD-ON-durvalumab-1108 following treatment with durvalumab 0.1 to 
10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W). The maximum observed 
concentration (Cmax) increased in an approximately dose-proportional manner over the dose range 

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of 0.1 to 15 mg/kg. The area under the concentration-time curve from 0 to 14 days (AUC0-14) 
increased in a greater than dose-proportional manner over the dose range of 0.1 to 3 mg/kg and 
increased dose-proportionally at ≥ 3 mg/kg. These results suggest durvalumab exhibits nonlinear 
PK likely due to saturable target-mediated CL at doses < 3 mg/kg and approaches linearity at doses 
≥ 3 mg/kg. Near complete target saturation (soluble programmed cell death ligand 1 [sPD-L1] and 
membrane bound) is expected with durvalumab ≥ 3 mg/kg Q2W. Exposures after multiple doses 
showed accumulation consistent with PK parameters estimated from the first dose. In addition, PK 
simulations indicate that following durvalumab 10 mg/kg Q2W dosing, > 90% of subjects are 
expected to maintain PK exposure ≥ 40 µg/mL throughout the dosing interval. 
 
As of 09Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 388 
subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg cohort) were 
ADA positive with an impact on PK/pharmacodynamics in 1 subject in the 3 mg/kg cohort. 
 
1.1.3 
Tremelimumab 
 
The non-clinical and clinical experience is fully described in the current version of the 
tremelimumab Investigator’s Brochure (See PDOL appendices). 
 
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte- 
associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152). This is an 
immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the treatment 
of cancer. 
 
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal, 
which limits T-cell activation. Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to B7 
ligands and enhance human T-cell activation as demonstrated by increased cytokine (interleukin 
[IL]-2 and interferon [IFN] gamma) production in vitro in whole blood or peripheral blood 
mononuclear cell (PBMC) cultures (Tarhini and Kirkwood 2008). In addition, blockade of CTLA- 
4 binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and 
anti-tumor activity in animal models, including killing of established murine solid tumors and 
induction of protective anti-tumor immunity. (Refer to the tremelimumab IB, Edition 6.0, for more 
information.) Therefore, it is expected that treatment with an anti-CTLA-4 antibody, such as 
tremelimumab, will lead to increased activation of the human immune system, increasing anti- 
tumor activity in patients with solid tumors. 
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab 
both as monotherapy and combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules. 
 
As of the data cutoff dates (1 November 2015 for monotherapy studies and 15 April 2015 to12 
July 2015 for combination therapy studies), 34 sponsored clinical studies have been conducted as 
part of the tremelimumab clinical development program. Of these, 13 studies have completedand 
21 are ongoing. Eight tremelimumab monotherapy studies have been completed and 3 are ongoing. 
As of the data cutoff date of 1 November 2015, 973 patients received tremelimumab in completed 
monotherapy studies and the ongoing Study D4881C00024 and 569 patients have been treated in 
the ongoing blinded Phase IIb monotherapy Study D4880C00003 [DETERMINE]). In the 3rd 

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ongoing monotherapy study (D4884C00001), no patients have been treated as of the data cutoff. 
In addition, approximately 59 patients have been treated with tremelimumab in monotherapy arms 
of combination studies. Five studies of tremelimumab in combination with other anticancer agents 
have been completed and 18 are ongoing. In total, 250 patients with a variety of tumour types have 
received tremelimumab in combination with other anticancer agents in these studies. Details on 
the safety profile of tremelimumab monotherapy are summarized in Section 0. Refer to the current 
tremelimumab IB (version 6.0) for a complete summary of non-clinical and clinical information; 
see Section 6.6 for guidance on management of tremelimumab-related toxicities. 
 
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days. 
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab. 
 
1.1.4 
Durvalumab in combination with tremelimumab 
 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 
2012) because the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, 
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy for 
the treatment of cancer. 
 
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in patients 
with advanced NSCLC. The dosing schedule utilized is durvalumab every 2 weeks (q2w) or every 
4 weeks (q4w) up to Week 50 and 48 (12 months), combined with tremelimumab q4w up to Week 
24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months. The study is ongoing 
and continues to accrue. 
 
Study D4190C00006: As of 20Feb2015, durvalumab PK (n = 55) and tremelimumab PK (n = 26) 
data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 9) following durvalumab 
every 4 weeks (Q4W) or Q2W dosing in combination with tremelimumab Q4W regimens. An 
approximately dose-proportional increase in PK exposure (Cmax and area under the concentration- 
time curve from 0 to 28 days [AUC0-28]) of both durvalumab and tremelimumab was observed 
over the dose range of 3 to 15 mg/kg durvalumab Q4W and 1 to 10 mg/kg tremelimumab Q4W. 
Exposures following multiple doses demonstrated accumulation consistent with PK parameters 
estimated from the first dose. It is to be noted that steady state PK parameters are based on limited 
numbers of subjects. The observed PK exposures of durvalumab and tremelimumab following 
combination were consistent with respective monotherapy data, indicating no PK interaction 
between these 2 agents. 
 
As of 20Feb2015, ADA data were available from 60 subjects for durvalumab and 53 subjects for 
tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for anti- 
durvalumab antibodies post treatment. One of 53 subjects was ADA positive for anti- 
tremelimumab antibodies post treatment. There was no clear relationship between ADA and the 
dose of either durvalumab or tremelimumab, and no obvious association between ADA and safety 
or efficacy. 
 
Durvalumab has also been combined with other anticancer agents, including gefitinib, dabrafenib, 
and trametinib. To date, no PK interaction has been observed between durvalumab and these 

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agents. 
 
1.2 
Research hypothesis 
 
To determine whether durvalumab plus tremelimumab can be safely administered and may 
induce augmented immunological and clinical responses in patients with metastatic castration- 
resistant prostate cancer. 
 
1.3 
Rationale for conducting this study 
 
As an antibody, that blocks the interaction between PD-L1 and its receptors, durvalumab may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic activity 
of anti-tumor T-cells. This hypothesis is supported by emerging clinical data from other mAbs 
targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical activity and a 
manageable safety profile (Brahmer et al 2012, Topalian et al 2012). Responses have been 
observed in patients with PD-L1-positive tumors and patients with PD-L1-negative tumors. In 
addition, durvalumab monotherapy has shown durable responses in NSCLC in Study 1108 (see 
Section 1.4.1.1). 
 
The rationale for combining durvalumab and tremelimumab is that the mechanisms of CTLA-4 
and PD-1 are non-redundant, suggesting that targeting both pathways may have additive or 
synergistic activity (Pardoll 2012). In fact, combining immunotherapy agents has been shown to 
result in improved response rates (RRs) relative to monotherapy. For example, the concurrent 
administration of nivolumab and ipilimumab to patients with advanced melanoma induced 
higher objective response rates (ORRs) than those obtained with single-agent therapy. 
Importantly, responses appeared to be deep and durable (Wolchok et al 2013). Similar results have 
been observed in an ongoing study of durvalumab + tremelimumab in NSCLC (Wolchok et al 2013).  
 
1.3.1 
Durvalumab + tremelimumab combination therapy dose rationale 
 
The durvalumab + tremelimumab doses and regimen selected for this study are based on the goal 
of selecting an optimal combination dose of durvalumab and tremelimumab that would yield 
sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an acceptable 
safety profile. 
 
Pharmacokinetics/Pharmacodynamics data 
Study D4190C00006 included dose cohorts with both a Q4W and a Q2W schedule of durvalumab 
in combination with a Q4W schedule of tremelimumab. The Q4W schedule was included toalign 
with the Q4W dosing of tremelimumab. PK simulations from durvalumab monotherapy data 
indicated that a similar area under the plasma drug concentration-time curve at steady state (AUCss; 
4 weeks) was expected following both 10 mg/kg Q2W and 20 mg/kg Q4W dosing with 
durvalumab. The observed durvalumab PK data from the D4190C00006 study were in line with 
the predicted monotherapy PK data developed pre-clinically and in line with that seen in the first- 
time-in-human (FTIH), single agent study (CD-ON-MEDI4736-1108) in patients with advanced 
solid tumors. This demonstrates similar exposure of durvalumab 20 mg/kg Q4W and 10 mg/kg 
Q2W, with no alterations in PK when durvalumab and tremelimumab (doses ranging from 1 to 3 
mg/kg) are dosed together. While the median maximum plasma concentration at steady state 

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(Cmax,ss) is expected to be higher with 20 mg/kg Q4W (approximately 1.5 fold) and median trough 
concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg Q2W 
(approximately 1.25 fold), this is not expected to impact the overall safety and efficacy profile, 
based on existing preclinical and clinical data. 
 
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab 
relative to the activity observed in patients treated with durvalumab monotherapy. There was 
evidence of augmented PDx activity relative to durvalumab monotherapywith combination doses 
containing 1 mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus 1 
mg/kg tremelimumab combinations. 
 
Clinical data 
In Study D4190C00006 various dose combinations have been explored, with doses of 
tremelimumab ranging from 1 to 10 mg/kg and doses of durvalumab ranging from 3 to 20 mg/kg. 
Tremelimumab was given on a Q4W schedule whilst durvalumab was explored in both a Q4W 
and Q2W schedule, with the goal of identifying the dose combination that best optimizes therisk: 
benefit profile in an acceptable range of PK and pharmacodynamic values. 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between 
the 10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the Q2W schedule, the number of patients reporting any AE, ≥ 
Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 
3 mg/kg tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. 
A similar pattern was noted in the Q4W regimens, suggesting that, as the dose of tremelimumab 
increased above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, 
the SAEs frequently attributed to immunotherapy, pneumonitis, colitis and other immune 
mediated events, were more commonly seen in cohorts using either 3 mg/kg or 10 mg/kg of 
tremelimumab compared to the 1-mg/kg dose cohorts. Together, these data suggest that a 
combination using a tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity 
when combined with durvalumab. As a result, all combination doses utilizing either the 3 or 10- 
mg/kg doses of tremelimumab were eliminated in the final dose selection. 
 
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab 
may not impact the safety of the combination as much as the tremelimumab dose. Further, safety 
data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in safety events 
with increasing dose of durvalumab. 
 
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had a tolerable safety profile, but still showedstrong 
evidence of clinical activity. No dose-limiting toxicities (DLTs) were reported in this cohort. 
 
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15- and 20-mg/kg durvalumab Q4W cohorts 
demonstrated objective responses at all doses of tremelimumab, and increasing doses of 
tremelimumab did not provide deeper or more rapid responses. 

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Efficacydata suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort may 
demonstrate equivalent clinical activity to other dose combinations. Of the 14 patients in this 
cohort, there were 4 patients (29%) with PR, 4 patients (29%) with SD, and 2 patients (14%) with 
PD. Two patients were not evaluable for response. 
 
Altogether, the data suggested that a 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose 
combination should be selected for further development. 
 
Refer to the current durvalumab Investigator’s Brochure for a complete summary of non-clinical 
and clinical information on the durvalumab + tremelimumab combination, including safety, 
efficacy and pharmacokinetics. 
1.3.2 
Rationale for 4 cycles of combination therapy followed by 
durvalumab monotherapy 
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting 
antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that patients 
responding to ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 22%. 
Furthermore, the survival curve in this population reached a plateau at 3 years and was maintained 
through 10 years of follow up (Schadendorf et al 2013). 
 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 
 
Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I dose-escalation and 
expansion study, and showed responses were maintained for a median of 22.94 months for 
melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), and 
12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of data analysis 
 
(Hodi et al 2014, Brahmer et al 2014, Drake et al 2013). Furthermore, responses were maintained 
beyond treatment discontinuation in the majority of patients who stopped nivolumab treatment 
(either due to protocol specified end of treatment, complete response [CR], or toxicity) for up to 
56 weeks at the time of data analysis (Topalian et al 2014). 
 
MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in which patients 
were dosed for a finite time period and responses maintained beyond treatment discontinuation 
have been reported (Herbst et al 2013, Wolchok et al 2013). 
 
Similar long term results may be expected with use of other immune-mediated cancer therapeutics 
including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies such as 
durvalumab, or the combination of the two. 
 
1.3.2.1 Durvalumab monotherapy dose rationale 
 
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced 
solid tumors and from a Phase I trial performed in Japanese patients with advanced solid tumor 
(D4190C00002). 

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PK/Pharmacodynamic data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging from 
0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear (dose-dependent) PK 
consistent with target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg Q2W, 
suggesting near complete target saturation (membrane-bound and sPD-L1), and further shows that 
the durvalumab dosing frequency can be adapted to a particular regimen given the linearity seen 
at doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is approximately 
21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over the dose range 
studied, consistent with engagement of durvalumab with PD-L1. A low level of immunogenicity 
has been observed. No patients have experienced immune-complex disease following exposure to 
durvalumab (For further information on immunogenicity, please see the current IB). 
 
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W. (For 
further information on PK observations in Study 006, please see the current IB). 
 
The observed durvalumab PK data from the combination study were well in line with the predicted 
monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen. 
 
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg (Fairman et al 2014). Multiple simulations indicate that a similar overall 
exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented 
by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W (~1.5 fold) and 
median Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 fold). Clinical activity with 
the 20 mg/kg Q4W dosing regimen is anticipated to be consistent with 10 mg/kg Q2W with the 
proposed similar dose of 20 mg/kg Q4W expected to (a) achieve complete target saturation in 
majority of patients; (b) account for anticipated variability in PK, pharmacodynamics, and clinical 
activity in diverse cancer populations; (c) maintain sufficient PK exposure in case of ADA impact; 
and (d) achieve PK exposure that yielded maximal antitumor activity in animal models. 
 
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg 
Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles, 
supporting further development with a dose of 20 mg/kg Q4W. 
 
Clinical data 
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical 
information including safety, efficacy and pharmacokinetics at the 20mg/kg Q4W regimen. 

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1.4 
Benefit/risk and ethical assessment 
 
1.4.1 
Potential benefits 
Durvalumab 
The majority of the safety and efficacy data currently available for durvalumab are based on the 
first time in-human, single-agent study (Study 1108) in patients with advanced solidtumors. Data 
from Study 1108 were presented at the European Society for Medical Oncology 2014 Congress. 
Overall, 456 of 694 subjects treated with durvalumab 10 mg/kg Q2W were evaluable for response 
(defined as having ≥ 24 weeks follow-up, measurable disease at baseline, and ≥ 1 follow-up scan, 
or discontinued due to disease progression or death without any follow-up scan). In PD-L1 
unselected patients, the objective response rate (ORR), based on investigator assessment per 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma 
(n = 23) to 20.0% in bladder cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) 
ranged from 4.2% in triple-negative breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous 
melanoma (n = 23). PD-L1 status was known for 383 of the 456 response evaluable subjects. 
Across the PD-L1-positive tumors, ORR was highest for bladder cancer, advanced cutaneous 
melanoma, hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), 
and squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the PD-L1- 
positive subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), NSCLC 
(n = 86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%). 
 
Tremelimumab 
 
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 15 mg/kg 
every 90 days to patients with refractory melanoma, an RR of 7% and a median OS of 10 months 
in the second-line setting (as compared to approximately 6 months with best supportive care 
reported from a retrospective analysis; (Korn et al 2008) were observed (Kirkwood et al2010). In 
a randomized, open-label, first-line Phase III study of tremelimumab (administered at 15 mg/kg 
every 90 days) versus chemotherapy (dacarbazine or temozolomide) in advanced melanoma 
(Study A3671009), results of the final analysis showed an RR of 11% and a median OS of 
12.58 months in this first-line setting as compared to 10.71 months with standard chemotherapy; 
however, these results were not statistically significant (Ribas et al 2013). Additionally, a Phase II 
maintenance study (Study A3671015) in patients with Stage IIIB or IV NSCLC who had responded 
or remained stable failed to achieve statistical significance. The primary endpoint of PFS at 3 
months was 22.7% in the tremelimumab arm (15 mg/kg) compared with 11.9% in the best 
supportive care arm (Study A3671015). 

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Durvalumab + tremelimumab 
 
The preclinical and clinical justification for this combination as noted in Section 1.1.4 also supports 
the synergy of this combination. Available data, such as those presented by (Wolchok et al 2013), 
suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may have profound and 
durable benefits in patients with melanoma (Wolchok et al 2013). Of the 102 subjects with 
advanced NSCLC treated with durvalumab in combination with tremelimumab in Study 
D4190C00006, 63 subjects with at least 16 weeks of follow-up were evaluable for response 
(defined as measurable disease at baseline and at least 1 follow-up scan; this included 
discontinuations due to disease progression or death without follow-up scan). Of the 63 evaluable 
subjects, 17 (27%) had a best overall response of PR, 14 (22%) had SD, 22 (35%) had PD, and 10 
(16%) were not evaluable. The ORR (confirmed and unconfirmed CR or PR) was 27% and the 
DCR (CR, PR, or SD) was 49% as assessed by RECIST v1.1. 
 
Current experience with single-agent IMT studies suggests that clinical responses may be restricted 
to a subset of any given patient population and that it might be beneficial to enrich the patient 
population by selecting patients likely to respond to therapy. To date, no assay has been established 
or validated, and no single approach has proven accurate, for patient enrichment for IMTs. 
However, independent data from multiple sources using different assays and scoring methods 
suggests that PD-L1 expression on tumor cells and/or tumor infiltrating cells may be associated 
with greater clinical benefit. 
 
Data from ongoing studies with durvalumab and other agents targeting the PD-1/PD-L1 pathway 
suggest, as shown in a number of tumor types (eg, NSCLC, renal cell carcinoma, and melanoma), 
that monotherapy may be more efficacious (in terms of ORR) in patients who are PD-L1-positive. 
 
Given these findings, a number of ongoing studies are assessing the activity of agents in patients 
with PD-L1–positive tumors. There is also an unmet medical need in patients with PD-L1– 
negative tumors that needs to be addressed. Data, as of 27 January 2015 from Study 006 show that 
with the addition of tremelimumab to durvalumab, the ORR can be increased to 25% in patients 
with PD-L1 negative NSCLC. As patients with PD-L1 positive disease can also have an increase 
in ORR, from 25% with durvalumab monotherapy, to 36% with the combination of durvalumab 
and tremelimumab, the study will enroll all patients with NSCLC, with an emphasis on those 
determined to be PD-L1 negative. 
 
1.4.2 
Potential risks 
Durvalumab 
Potential risks, based on the mechanism of action of durvalumab and related molecules, include 
immune-mediated reactions, such as enterocolitis, dermatitis, hepatitis/hepatotoxicity, 
endocrinopathy, pneumonitis, and neuropathy or neurologic events. Additional important potential 
risks include infusion-related reactions, hypersensitivity, anaphylaxis or serious allergic reactions, 
serious infections, and immune complex disease. 
 
 

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Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 694 
subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-durvalumab- 1108 
has been broadly consistent with that of the overall 1,279 subjects who have received durvalumab 
monotherapy (not including subjects treated with blinded investigational product) across the 
clinical development program. The majority of treatment-related AEs were manageable with dose 
delays, symptomatic treatment, and in the case of events suspected to have an immune basis, the 
use of established treatment guidelines for immune-mediated toxicity. As of 07May2015, among the 
694 subjects treated with durvalumab 10 mg/kg Q2W in Study CD-ON-durvalumab- 1108, a total 
of 378 subjects (54.5%) experienced a treatment-related AE, with the most frequent (occurring in 
≥ 5% of subjects) being fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite 
(6.8%), pruritus (6.3%), rash (6.1%), and vomiting (5.0%). A majority of the treatment- related 
AEs were Grade 1 or Grade 2 in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). 
Treatment-related ≥ Grade 3 events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 
subjects, 1.7%); increased aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma- 
glutamyltransferase (GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 
subjects, 0.7%); and colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% 
each). Six subjects had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, 
increased AST, dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a 
treatment-related Grade 5 event (pneumonia). Treatment-related serious adverse events (SAEs) 
that occurred in ≥ 2 subjects were colitis and pneumonitis (3 subjects each). A majority of the 
treatment-related SAEs were ≥ Grade 3 in severity and resolved with or without sequelae. AEs that 
resulted in permanent discontinuation of durvalumab were considered as treatment related in 
18 subjects (2.6%), with colitis being the most frequent treatment-related AE resulting in 
discontinuation (3 subjects). A majority of the treatment-related AEs resulting in discontinuation 
of durvalumab were ≥ Grade 3 in severity and resolved with or without sequelae. 
 
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in Study CD- 
ON-durvalumab-1108 is generally consistent with that of Study D4191C00003/ATLANTIC in 
subjects with locally advanced or metastatic non-small-cell lung cancer (NSCLC) treated with 
durvalumab 10 mg/kg Q2W. As of 05May2015, 264 of 303 subjects (87.1%) reported any AE in 
Study D4191C00003/ATLANTIC. Overall, events reported in ≥ 10% of subjects were dyspnea 
(18.8%), fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia (12.2%), asthenia 
(11.9%), and nausea (11.2%). Nearly two-thirds of the subjects experienced AEs that were Grade 
1 or 2 in severity and manageable by general treatment guidelines as described in the current 

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durvalumab study protocols. Grade 3 or higher AEs were reported in 107 of 303 subjects (35.3%). 
A total of 128 subjects (42.2%) reported AEs that were considered by the investigator as related 
to investigational product. Treatment-related AEs (all grades) reported in ≥ 2% of subjects were 
decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); 
diarrhea, hyperthyroidism, hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight 
decreased (2.3%); and vomiting (2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects 
were pneumonitis (3 subjects) and increased GGT (2 subjects). There was no treatment-related 
Grade 4 or 5 AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that occurred in 
≥ 1.0% of subjects were dyspnea (6.6%); pleural effusion, general physical health deterioration 
(2.3% each); pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, 
respiratory failure, disease progression (1.0% each). Nine subjects had an SAE considered by the 
investigator as related to durvalumab. Each treatment-related SAE occurred in 1 subject each with 
the exception of pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have 
died due to an AE (pneumonia [3 subjects]; general physical health deterioration, disease 
progression, hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, 
cardiopulmonary arrest [verbatim term (VT)], hepatic failure, and sepsis [1 subject each]). None 
of these events was considered related to durvalumab. Twenty-three of 303 subjects (7.6%) 
permanently discontinued durvalumab treatment due to AEs. Events that led to discontinuationof 
durvalumab in ≥ 2 subjects were dyspnea, general physical health deterioration, and pneumonia. 
Treatment-related AEs that led to discontinuation were increased ALT and increased hepatic 
enzyme, which occurred in 1 subject each. 
 
Tremelimumab 
 
Potential risks, based on the mechanism of action of tremelimumab and related molecules 
(ipilimumab) include potentially immune-mediated gastrointestinal (GI) events including 
enterocolitis, intestinal perforation, abdominal pain, dehydration, nausea and vomiting, and 
decreased appetite (anorexia); dermatitis including urticaria, skin exfoliation, and dry skin; 
endocrinopathies including hypophysitis, adrenal insufficiency, and hyperthyroidism and 
hypothyroidism; hepatitis including autoimmune hepatitis and increased serum ALT and AST; 
pancreatitis including autoimmune pancreatitis and lipase and amylase elevation; respiratorytract 
events including pneumonitis and interstitial lung disease (ILD); nervous system events including 
encephalitis, peripheral motor and sensory neuropathies, and Guillain-Barré syndrome; cytopenias 
including thrombocytopenia, anemia, and neutropenia; infusion-related reactions; anaphylaxis; 
and serious allergic reactions. 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 appears to be confined to patients with melanoma). Overall, 944 of the 973 patients (97.0%) 
treated with tremelimumab monotherapy as of the data cutoff date of 12 

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November 2014 (for all studies except D4190C00006 that has a cutoff date of 04 December 2014 
and not including 497 patients who have been treated in the ongoing blinded Phase IIb Study 
D4880C00003) experienced at least 1 AE. The events resulted in discontinuation of tremelimumab 
in 10.0% of patients, were serious in 36.5%, were Grade ≥3 in severity in 49.8%, were fatal in 
67.7%, and were considered to be treatment related in 79.1% of patients. The frequency of any 
AEs and Grade ≥3 AEs was generally similar across the tremelimumab dose groups. However, a 
higher percentage of patients in the 10 mg/kg every 28 days and 15 mg/kg every 90 days groups 
compared with the All Doses <10 mg/kg group experienced treatment-related AEs, SAEs, AEs 
resulting in discontinuation of investigational product (IP), and deaths. 
 
Durvalumab + tremelimumab 
 
No safety studies in animals have been performed combining tremelimumab with durvalumab. As 
both CTLA-4 and PD-L1 have mechanisms of actions that enhance activation of immune cells, 
their potential to induce cytokine release was tested in a whole-blood assay system. Durvalumab 
and tremelimumab, either alone or in combination, did not induce cytokine release in blood from 
any donor. 
 
Study D4190C00006: The safety profile of durvalumab and tremelimumab combination therapy 
in the 102 subjects with advanced NSCLC in Study D4190C00006 is generally consistent with that 
observed across 177 subjects treated with durvalumab and tremelimumab combination therapy (not 
including subjects treated with blinded investigational product). As of 15Apr2015, 95 of 102 
subjects (93.1%) reported at least 1 AE. All subjects in the tremelimumab 3 and 10 mg/kg dose 
cohorts experienced AEs; subjects in the durvalumab 20 mg/kg and tremelimumab 1 mg/kg Q4W 
cohort experienced the lowest AE rate (77.8%). Treatment-related AEs were reported in 74 of 102 
subjects (72.6%), with events occurring in > 10% of subjects being diarrhea (27.5%), fatigue 
(22.5%), increased amylase and pruritus (14.7% each), rash (12.7%), colitis (11.8%), and increased 
lipase (10.8%). Treatment-related ≥ Grade 3 AEs reported in ≥ 5% of subjects were colitis (8.8%), 
diarrhea (7.8%), and increased lipase (5.9%). Five subjects reported treatment- related Grade 4 
events (sepsis, increased ALT, and increased AST in 1 subject; increased amylase in 2 subjects; 
myasthenia gravis in 1 subject; and pericardial effusion in 1 subject) and 2 subjects had treatment- 
related Grade 5 events (polymyositis and an uncoded event of neuromuscular disorder [VT]); the 
Grade 4 event of myasthenia gravis and Grade 5 polymyositis occurred in 1 subject. There were 2 
subjects (both in the MEDI4736 20 mg/kg + tremelimumab 3 mg/kg Q4W cohort) with dose- 
limiting toxicities (DLTs): 1 subject with Grade 3 increased AST, and 1 subject with Grade 3 
increased amylase and Grade 4 increased lipase. Fifty-six subjects (54.9%) reported SAEs, with 
events occurring in > 5% of subjects being colitis (9.8%) and diarrhea (7.8%). Thirty- six subjects 
(35.3%) experienced treatment-related SAEs. Twenty-seven subjects (26.5%) permanently 
discontinued treatment due to AEs. Treatment-related AEs resulting in discontinuation in ≥ 2 
subjects were colitis (7 subjects), pneumonitis (5 subjects), diarrhea (3 

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subjects), and increased AST (2 subjects).Additional safety results from this study are presented 
in Section 0 and the durvalumab IB. 
 
In the literature (Wolchok et al 2013), using the combination of the same class of drugs (eg, anti-
PD-1 and anti-CTLA4 antibodies), specifically nivolumab + ipilimumab in a study involving 
patients with malignant melanoma, the safety profile of this combination had shown occurrences 
of AEs assessed by the Investigator as treatment-related in 93% of treated patients, with the most 
frequent events being rash (55% of patients), pruritus (47% of patients), fatigue (38% of patients), 
and diarrhea (34% of patients). Grade 3 or 4 AEs, regardless of causality, were noted in 72% of 
patients, with Grade 3 or 4 events assessed bythe Investigator as treatment-related in 53%. The most 
frequent of these Grade 3 or 4 events assessed by the Investigator as treatment- related include 
increased lipase (in 13% of patients), AST (in 13%), and ALT levels (in 11%). Frequent Grade 3 
or 4 selected AEs assessed by the Investigator as treatment-related in the combination therapy 
included hepatic events (in 15% of patients), GI events (in 9%), and renal events (in 6%). Isolated 
cases of pneumonitis and uveitis were also observed. 
 
Fixed Dosing for durvalumab and tremelimumab 
 
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected 
to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were 
simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body 
WT-based and fixed dosing regimens yield similar median steady state PK concentrations with 
slightly less overall between-subject variability with fixed dosing regimen. 
 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [Wang 
et al. 2014]. Population PK model indicated minor impact of body WT on PK of tremelimumab 
(coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on 
median body WT of ~75 kg) regimens were compared using predicted PK concentrations (5th, 
median and 95th percentiles) using population PK model in a simulated population of 1000 patients 
with body weight distribution of 40 to 120 kg. Similar to durvalumab, simulations indicated that 
both body WT-based and fixed dosing regimens of tremelimumab yield similar median steady 
state PK concentrations with slightly less between-subject variability with fixed dosing regimen. 
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 2012, 
Narwal et al 2013]. Wang and colleagues investigated 12 monoclonal antibodies and found that 

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fixed and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies. In addition, they investigated 18 therapeutic proteins and peptides and showed that 
fixed dosing performed better for 12 of 18 in terms of reducing the between-subject variability in 
pharmacokinetic/pharmacodynamics parameters (Zhang et al 2012). 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and variability, we 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg 
Q4W) is included in the current study. 
 
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30kg 
body weight due to endotoxin exposure. Patients with a body weight less than or equal to 30 kg 
should be dosed using a weight-based dosing schedule. 
 
 
2.0 
STUDY OBJECTIVE 
 
2.1 
Primary objective(s) 
 
• To evaluate the safety and tolerability of durvalumab plus tremelimumab in patients with 
metastatic castration-resistant prostate cancer. 
 
2.2 
Secondary Objective(s) 
 
• To assess the efficacy of durvalumab plus tremelimumab in patients with metastatic 
castration-resistant prostate cancer. 
• To explore immunological changes in peripheral blood and tissue (e.g. peripheral blood 
cluster of differentiation (CD)4+(Inducible COStimulator (ICOS)+ T cells, CD3 
expression in tissue) in response to durvalumab plus tremelimumab in patients with 
metastatic castration-resistant prostate cancer. 
 
3.0 
STUDY DESIGN 
 
3.1 
Overview of study design 
 
This is an open-label, single center, Phase II pilot study to explore the link between 
immunological changes and efficacy of durvalumab (1500 mg IV q4w) in combination with 
tremelimumab (75 mg IV q4w) for up to 4 doses/cycles each followed by durvalumab 1500 mg 
IV q4w for up to a total of 8 months [9 additional doses/cycles]) in chemotherapy-naïve men with 
metastatic CRPC.  
This study will enroll approximately 27 patients. 
 
 
 
 

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3.2 
Study schema 
 
Figure 1. 
 
 
3.3 
Study Oversight for Safety Evaluation 
 
Toxicity will be monitored in all patients who receive at least one dose of tremelimumab, even if 
the patient is not evaluable for the biomarker or efficacy endpoint. Further details are included in 
Section 11.2.2. 
 
4.0 
PATIENT 
SELECTION, 
ENROLLMENT, 
RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL 
Each patient must meet all of the inclusion criteria (Section 4.1) and none of the exclusion criteria 
(Section 4.2) for this study. Under no circumstances will there be exceptions to this rule. 
 
4.1 
Inclusion criteria 
 
For inclusion in the study, patients should fulfill the following criteria: 
 
1. 
Written informed consent. 
 
2. 
Age > 18 years at time of study entry. 
 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 
4. 
Life expectancy of > 52 weeks. 
 
5. 
Adequate normal organ and marrow function as defined below: 
 
− 
Hemoglobin ≥ 11.0 g/dL. 
 
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3). 
 
− 
Platelet count ≥ 100 x 109/L (>100,000 per mm3). 
 
− 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not 

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apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis 
or hepatic pathology), who will be allowed only in consultation with their physician. 
 
− 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal 
− 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance: 
Males 
 
Creatinine    CL   = 
Weight  (kg)  x   (140  -  Age)          
(mL/min) 
72 x serum creatinine (mg/dL) 
 
6. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up. 
 
7. 
Consent to MD Anderson laboratory protocol PA13-0291and LAB02-152. 
 
8. 
Willing to have peripheral blood mononuclear cells and bone marrow biopsies to be 
collected prior to receiving the first dose of durvalumab and tremelimumab, after 2- 
doses and 4-doses of durvalumab and tremelimumab, after 2nd treatment administration 
and 4th treatment administration. 
 
9. 
Histologically or cytologically confirmed adenocarcinoma of the prostate. 
 
10. 
Evidence of metastatic disease to the bone seen on most recent bone scan, CT scan 
and/or MRI. 
11. 
Asymptomatic or minimally symptomatic patients (do not require narcotics for prostate 
cancer-related pain). 
 
12. 
Tumor progression while on hormone therapy with castrate levels serum testosterone (≤ 
1.7 nmol/L or 50 ng/dL) defined by PSA and/or radiographic criteria according to the 
Prostate Cancer Working Group 3 (PCWG3). Castrate levels of testosterone must be 
maintained by surgical or medical means throughout the conduct of the study. 
 
4.2 
Exclusion criteria 
 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
 
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site), previous enrollment in the present study. 
 
2. Participation in another clinical study with an investigational product during the last 4 weeks. 
 
3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti- 
CTLA4, including tremelimumab. 
 

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4. History of another primary malignancy except for: 
 
- Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of study drug and of low potential risk for recurrence. 
 
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease. 
 
- Adequately treated carcinoma in situ without evidence of disease (eg, superficial 
bladder cancer). 
 
5. Evidence of visceral metastasis to the liver. 
 
6. Prior use of taxane-based chemotherapy, for treatment of castrate resistant prostate cancer. 
 
7. Receipt of the last dose of anti-cancer therapy (immunotherapy, endocrine therapy [eg, 
abiraterone acetate, enzalutamide], targeted therapy, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) ≤ 28 days prior to the first dose of study 
drug. (With the exception of those treatments described in exclusion #3) 
 
8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of durvalumab or tremelimumab. Note: Local surgery of isolated lesions for palliative 
intent is acceptable. 
 
9. QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms. Any 
clinically significant abnormalities detected, require triplicate ECG results and a mean QT 
interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated from 
3 ECGs. 
 
10. Current or prior use of immunosuppressive medication within 28 days before the first dose 
of durvalumab or tremelimumab, with the exceptions of: 
 
- intranasal and inhaled corticosteroids or systemic corticosteroids at physiological 
doses, which are not to exceed 10 mg/day of prednisone, or an equivalent 
corticosteroid or steroids as pre-medication for hypersensitivity reactions (eg CT 
scan premedication) 
 
11. Any unresolved toxicity (CTCAE Grade ≥2) from previous anti-cancer therapy. Subjects 
with irreversible toxicity that is not reasonably expected to be exacerbated by the 
investigational product may be included (e.g., hearing loss, peripherally neuropathy). 
 
12. Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, 
uveitis, etc]). The following are exceptions to this criterion: 
 
− 
Patients with vitiligo or alopecia. 
− 
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 

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hormone replacement. 
 
− 
Any chronic skin condition that does not require systemic therapy. 
− 
Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician. 
 
− 
Patients with celiac disease controlled by diet alone. 
 
− 
Subjects with history of diverticulitis may be included only after consultation and 
approval of the study physician 
 
13. History of primary immunodeficiency. 
 
14. History of allogeneic organ transplant. 
 
15. History of hypersensitivity to the combination of durvalumab and tremelimumab. 
 
16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including 
any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human 
immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance 
with study requirements or compromise the ability of the subject to give written informed consent. 
 
17. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS). Known history of positive test for hepatitis B virus (HBV) 
using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV 
ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection. 
 
18. History of leptomeningeal carcinomatosis. 
 
19. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days 
of receiving durvalumab or tremelimumab. 
 
20. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
21. Brain metastases or spinal cord compression unless asymptomatic or treated and stable off 
steroids and anti-convulsants for at least 28 days prior to study treatment start. Patients with 
suspected brain metastases at Screening should have a CT/MRI of the brain prior to study 
entry. 
 
22. Subjects with uncontrolled seizures. 
 
23. Male patients of reproductive potential who are not willing to employ effective birthcontrol 
from screening to 180 days after the last dose of durvalumab + tremelimumab combination 
therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer 
time period. 
 

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24. A malignancy [other than the one treated in this study] which required radiotherapy or systemic 
treatment within the past 5 years, or has a ≥ 30% probability of recurrence within 24 months (except 
for non-melanoma skin cancer or Ta urothelial carcinomas). 
 
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3 
 
If a patient withdraws from participation in the study, then his enrollment code cannot be reused. 
Withdrawn patients will not be replaced. 
 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study 
 
Permanent discontinuation of either durvalumab plus tremelimumab or durvalumab. 
An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question: 
1. Withdrawal of consent or lost to follow-up. 
2. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing. 
3. Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk. 
4. Any AE that meets criteria for discontinuation as defined in the Dosing Modification and 
Toxicity Management Guidelines (see Table 3). 
5. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; eg, refusal to adhere to scheduled visits. 
6. Initiation of alternative anticancer therapy including another investigational agent. 
7. Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with durvalumab + tremelimumab. 
8. Withdrawal of consent from further treatment with IP. The patient is, at any time, free to 
discontinue treatment, without prejudice to further treatment. A patient who discontinues 
treatment is normally expected to continue to participate in the study unless they 
specifically withdraw their consent to further participation in any study procedures and 
assessments 
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as having 
permanently discontinued treatment. 
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10.1 and Table 2, including the collection of any protocol- 
specified blood specimens, unless consent is withdrawn or the subject is lost to follow-up or 
enrolled in another clinical study. All subjects will be followed for survival. Subjects who 
decline to return to the site for evaluations will be offered follow-up by phone per the schedule 
in table 2 as an alternative. 
 
4.4 
Replacement of subjects 
 
A total of 20 biomarker-evaluable patients are planned to be enrolled on this trial. The number 
is small as a proof-of-concept study utilizing immune biomarkers as important secondary 
endpoints. To be evaluable for the secondary objectives, a patient needs to receive 2 doses of 

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durvalumab + tremelimumab, have immune markers measured, and have at least one follow-up 
for clinical outcome measures. Up to 7 patients who do not remain on study will be allowed to 
achieve 20 evaluable patients, for a maximum enrollment of 27 patients. All additional patients 
who received at least 1 dose of study drug will still be counted in safety analyses. 
 
5.0 
INVESTIGATIONAL PRODUCT(S) 
 
5.1 
Durvalumab and tremelimumab 
 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply durvalumab 
and tremelimumab to the investigator as a solution for infusion after dilution. 
 
List of investigational products for this study 
 
Investigational product 
Dosage form and strength 
Manufacturer 
Durvalumab 
1500 mg, solution, IV 
AstraZeneca/MedImmune 
Tremelimumab 
75 mg, solution, IV 
AstraZeneca/MedImmune 
 
5.1.1 
Formulation/packaging/storage 
 
Durvalumab 
 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 
275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The 
nominal fill volume is 10 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Durvalumab must be used within the individually assigned expiry 
date on the label. 
 
Tremelimumab 
 
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial solution for infusion after 
dilution. The solution contains 20 mg/mL of tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM disodium 
edetate dihydrate (EDTA); it has a pH of 5.5. The nominal fill volume is 20 mL. Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Tremelimumab 
must be used within the individually assigned expiry date on the label. 
 
6.0 
TREATMENT PLAN 
 
6.1 
Subject enrollment 
 
All screening and enrollment procedures will be performed according to the assessment schedule 
in (Table 1). 
 
Written informed consent and any locally required privacy act document authorization must be 
obtained prior to performing any protocol-specific procedures, including screening/baseline 

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evaluations. All patients will be required to provide consent to supply a sample of their tumor for 
entry into this study. 
 
All screening/baseline procedures, must be performed within 28 days before the first dose of 
treatment. Screening/baseline evaluations may be performed over more than 1 visit. Informed 
consent may be obtained prior to the 28-day screening window to permit tumor biopsy sample 
acquisition. 
 
6.2 
Dose and treatment regimens 
 
6.2.1 
Treatment regimens 
 
Durvalumab + tremelimumab combination therapy 
 
Patients in the combination of durvalumab + tremelimumab portion of the regimen will receive 
1500 mg durvalumab via IV infusion q4w and 75 mg tremelimumab via IV infusion q4w for up to 
4 doses. Subjects experiencing adverse events (AEs) related to combination dose therapy (Part 1) 
that do not meet dose discontinuation criteria, may proceed to durvalumab monotherapy dosing 
(Part 2) without completing all 4 combination doses. A minimum of two combination cycles are 
required to proceed to durvalumab monotherapy. Additional durvalumab monotherapy doses will 
be given to complete a total of 13 treatment doses (including combination therapy). Tremelimumab 
will be administered first. Durvalumab infusion will start approximately 1 hour after the end of 
tremelimumab infusion. The duration will be approximately 1 hour for each infusion. A 1-hour 
observation period is required after the first infusion of durvalumab and tremelimumab. If no 
clinically significant infusion reactions are observed during or after the first cycle, subsequent 
infusion observation periods can be conducted at the Investigator’s discretion. 
 
Durvalumab monotherapy 
 
Starting on 4 weeks after last dose of combination therapy patients will begin to receive 1500 mg 
durvalumab via IV infusion q4w for up 11 doses. The duration of the infusion will last 
approximately 1 hour. The observation period following infusion will be at (suggested 30 minutes 
post infusion). 
 
6.2.2 
Criteria for retreatment 
 
Retreatment is allowed (once only) for patients meeting the retreatment criteria below. The same 
treatment guidelines followed during the initial 12-month treatment period will be followed during 
the retreatment period, including the same dose and frequency of treatments and the same schedule 
of assessments. 
 
Patients may undergo retreatment in 2 clinical scenarios, described below: 
 
1. Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the end 
of the 12-month treatment period may restart treatment with the combination upon evidence of 
PD, with or without confirmation according to RECIST 1.1, during follow-up. 
 

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2. Patients who have received at least 2 dosing of cycles of the combination of durvalumab + 
tremelimumab portion of the regimen (with clinical benefit per Investigator judgment), but 
subsequently have evidence of PD during the durvalumab monotherapy portion of the 
regimen, with or without confirmation according to RECIST 1.1, may restart treatment 
with the combination. 
 
o Before restarting treatment, the Investigator should ensure that the patient: Does 
not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient 
 
o Still fulfils the eligibility criteria for this study, including re-consenting to restart 
durvalumab and tremelimumab 
 
o Has not have received an intervening systemic anticancer therapy after their 
assigned treatment discontinuation. 
 
o Has had a baseline tumor assessment within 28 days of restarting treatment; all 
further scans should occur with the same frequency as during the initial 12 months 
of treatment until study treatment is stopped (maximum of 12 months of further 
treatment). 
 
During the retreatment period, patients receiving durvalumab + tremelimumab may resume 
durvalumab dosing at 1500 mg q4w with 75 mg of tremelimumab q4w for up to 4 doses. Subjects 
experiencing adverse events (AEs) related to combination dose therapy that do not meet dose 
discontinuation criteria, may proceed to durvalumab monotherapy dosing without completing all 
4 combination doses. Patients will then continue with durvalumab monotherapy (a minimum of 
two combination cycles are required to proceed to durvalumab monotherapy) at 1500 mg q4w, 
beginning at 4 weeks after the last dose of combination therapy (up to a total of 11 durvalumab 
monotherapy doses). 
 
Treatment through progression is at the Investigator’s discretion, and the Investigator should 
ensure that patients do not have any significant, unacceptable, or irreversible toxicities that indicate 
that continuing treatment will not further benefit the patient. A patient with a confirmed 
progression receiving durvalumab + tremelimumab cannot continue therapy or obtain retreatment 
if dosing is ongoing in the combination portion of therapy (q4w dosing) and progression occurs in 
a target lesion that has previously shown a confirmed response. 
 
A patient with confirmed progression cannot continue therapy or obtain retreatment with a regimen 
if dosing for the same regimen is ongoing and the progression occurs in target lesions that have 
previously shown a confirmed response of complete response or partial response. 
 
Patients who the IND Office and/or the Investigator determine may not continue treatment will 
enter follow-up. 
 
Study drug preparation of durvalumab and tremelimumab 
 
Based on average body WT of 75 kg, 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) 
and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the current study. 

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Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared by the Investigator’s designated IP 
manager using aseptic technique. 
 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. 
 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline or dextrose, with a final durvalumab concentration ranging from 1 to 
20 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. 
Remove 30.0 mL of IV solution from the IV bag prior to addition of durvalumab. Next, 
30.1 mL of durvalumab (ie, 1500 mg of durvalumab) is added to the IV bag such that final 
concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag. 
 
Patient weight at baseline should be used for dosing calculations unless there is a ≥10% change in 
weight. Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard. 
 
Calculate the dose volume of durvalumab and tremelimumab and number of vials needed for the 
subject to achieve the accurate dose. 
 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
durvalumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes 
is considered a deviation. 
 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or complete 
the infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. 
 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. The table below summarizes time 
allowances and temperatures. 
 
Durvalumab hold and infusion times 
 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in the 

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table, a new dose must be prepared from new vials. Durvalumab does not contain preservatives, 
and any unused portion must be discarded. 
 
Preparation of tremelimumab doses for administration with an IV bag 
The dose of tremelimumab for administration must be prepared by the Investigator’s designated 
IP manager using aseptic technique. 
 
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F-46°F) 
until needed. If storage time exceeds these limits, a new dose must be prepared from new vials. 
The refrigerated infusion solutions in the prepared final IV bag should be equilibrated at room 
temperature for about 2 hours prior to administration. Tremelimumab does not contain 
preservatives and any unused portion must be discarded. 
 
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have 
been observed. Doses of 75 mg tremelimumab for patients >30 kg will be administered using an 
IV bag containing 0.9% (w/v) saline or dextrose, with a final tremelimumab concentration ranging 
from 0.1 mg/mL to 10 mg/mL, and delivered through an IV administration set with a 0.2 μm or 
0.22 μm in-line filter. Remove 3.8 mL of IV solution from the IV bag prior to addition of 
tremelimumab. Next, 3.8 mL of tremelimumab (ie, 75 mg of tremelimumab) is added to the IV 
bag such that final concentration is within 0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 500 
mL). Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
Patient weight at baseline should be used for dosing calculations unless there is a ≥10% change in 
weight. Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard. 
 
Tremelimumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
tremelimumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes 
is considered a deviation. 
 
The IV line will be flushed with a volume of 0.9% (w/v) saline equal to the priming volume of 
the infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document if 
the line was not flushed. 
 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. The table below summarizes time 
allowances and temperatures. 
 
Tremelimumab hold and infusion times 
 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 
 

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In the event that either preparation time or infusion time exceeds the time limits outlined in the 
table, a new dose must be prepared from new vials. Tremelimumab does not contain 
preservatives, and any unused portion must be discarded. 
6.2.3 
Durvalumab (MEDI4736) + tremelimumab combination therapy 
dosing schedule 
 
 
6.2.4 
Monitoring of dose administration 
 
Patients will be monitored during and after the infusion with assessment of vital signs (blood 
pressure and pulse) at the times specified in the Study Protocol. 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the initial 
rate until completion of the infusion. For patients with a ≤Grade 2 infusion-related reaction, 
subsequent infusions may be administered at 50% of the initial rate. Acetaminophen and/or an 
antihistamine (eg, diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator. If the infusion-related reaction is ≥Grade 3 or 
higher in severity, study drug will be discontinued. 
 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and 
medical equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis. The study site must have immediate 
access to emergency resuscitation teams and equipment in addition to the ability to admit patients 
to an intensive care unit if necessary 
 
6.2.5 
Accountability and dispensation 
 
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the Investigational Pharmacy standards. Study-site personnel must not combine 

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contents of the study drug containers. 
 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. 
 
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
 
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. The site will account for all investigational study drug dispensed 
and also for appropriate destruction. 
 
6.3 
Dose Modification and Toxicity Management 
 
6.3.1 
Durvalumab and tremelimumab 
 
For adverse events (AEs) that are considered at least partly due to administration of durvalumab 
the following dose adjustment guidance may be applied: 
 
• Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
• If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab or tremelimumab along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are permitted 
for durvalumab and tremelimumab (see Table 3). 
• All dose modifications should be documented with clear reasoning and documentation of 
the approach taken. 
 
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued. 
 
Following the first dose of durvalumab or tremelimumab, subsequent administration of 
durvalumab or tremelimumab can be modified based on toxicities observed. Dose reductions are 
not permitted. 
 
Based on the mechanism of action of durvalumab or tremelimumab leading to T-cell activation 
and proliferation, there is the possibility of observing immune related Adverse Events (irAEs) 
during the conduct of this study. Potential irAEs include immune-mediated enterocolitis, 
dermatitis, hepatitis, and endocrinopathies. Subjects should be monitored for signs and 
symptoms of irAEs. In the absence of an alternate etiology (e.g., infection or PD) signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to be 
immune-related. 
 

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Dose modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
Table 3. 
 
In addition, management guidelines for adverse events of special interest (AESIs) are detailed in 
Table 3. All toxicities will be graded according to NCI CTCAE v4.03 other version. 
7.0 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 
Restrictions during the study 
 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
 
Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use 2 acceptable methods of effective contraception from screening through 180 days after receipt 
of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of 
the final dose of durvalumab monotherapy, whichever is the longer time period. 
 
Restrictions relating to concomitant medications are described in (Section 7.2). 
 
Highly Effective Methods of Contraceptiona 
 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (eg, Mirena®)b 
• 
Etonogestrel implants: e.g. Implanon or 
Norplan 
• 
Intravaginal device: e.g. ethinylestradiol and 
etonogestrel 
• 
Medroxyprogesterone injection: e.g. Depo- 
Provera 
• 
Normal and low dose combined oral 
contraceptive pill 
• 
Norelgestromin/ethinylestradiol transdermal 
system 
• 
Cerazette (desogestrel) 
a Highly effective (i.e. failure rate of <1% per year) 
b This is also considered a hormonal method 
Blood donation 
All patients: Patients should not donate blood or blood components while participating in this study 
and through 180 days after receipt of the final dose of durvalumab + tremelimumab combination 
therapy or 90 days after receipt of the final dose of durvalumab or until alternate anti-cancer 
therapy is started. 
 
7.2 
Concomitant treatment(s) 
 
The concurrent use of all other drugs, over-the-counter medications, or alternative therapies 

Protocol 2016-0769 
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including herbal supplements will be captured in the electronic medical record. 
 
The patient will provide a list of medications, including over the counter agents, herbal 
preparations, taken prior to enrollment, and will update the list during clinic visits while on 
treatment. Concurrent medications related to co-morbidity (e.g. hypertension, diabetes, etc.) will 
be recorded in Prometheus. The name, dose, date start and stop (as accurately as possible) along 
with indication of the medication will be collected. 
 
Supportive medications, pre-medications routinely prescribed prior to chemotherapy or 
immunotherapy infusion to mitigate reactions, hydration, or routine surgical drugs will not be 
recorded in the Prometheus. 
 
Restricted, prohibited, and permitted concomitant medications are described below. See Table 3 
for guidance on management of IP-related toxicities. 
 
7.2.1 
Permitted concomitant medications 
 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed in (Section 7.2.2). 
 
7.2.2 
Excluded Concomitant Medications 
 
The following medications are considered exclusionary during the study. 
 
1. Any investigational anticancer therapy other than the protocol specified therapies. 
 
2. Any concurrent chemotherapy, radiotherapy (except when radiotherapy is used to palliate 
bone lesions involving ≤ 25% of the bone marrow), immunotherapy, biologic or 
hormonal therapy for cancer treatment, other than any stated comparator or combination 
regimens. Concurrent use of hormones for noncancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable. NOTE: Local treatment of 
isolated lesions for palliative intent is acceptable (e.g., by local surgery or radiotherapy) 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted. A temporary period 
of steroids will be allowed for different indications, at the discretion of the principal 
investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc). 
 
Live attenuated vaccines within 30 days of durvalumab and tremelimumab dosing (ie, 30 
days prior to the first dose, during treatment with durvalumab and tremelimumab for 30 
days post discontinuation of durvalumab and tremelimumab. Inactivated vaccines, such 
as the injectable influenza vaccine, are permitted. 
 
 

Protocol 2016-0769 
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Prohibited and Rescue Medications 
 
Prohibited medication/class of drug: 
Usage: 
Additional investigational anticancer therapy 
concurrent with those under investigation in 
this study 
Should not be given whilst the patient is on IP 
treatment 
mAbs against CTLA-4, PD-1, or PD-L1other 
than those under investigation in this study 
Should not be given whilst the patient is on IP 
treatment through 90 days after the last dose of IP. 
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy for non-target 
lesions, eg, radiotherapy, surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment 
Should not be given whilst the patient is on IP 
treatment (including SoC). (Concurrent use of 
hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.) 
Immunosuppressive medications, including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
its equivalent, methotrexate, azathioprine, and 
tumor necrosis factor α blockers 
Should not be given whilst the patient is on IP 
treatment (including SoC). (Use of 
immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies 
is acceptable. In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC) during the study 
 
Rescue/supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary by the Investigator to 
provide adequate prophylactic or supportive 
care, except for those medications identified as 
“prohibited” as listed above 
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc]) 
Should be used when necessary for all patients 
 
8.0 
STUDY PROCEDURES 
 
8.1 
Schedule of study procedures 
 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments. Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated. The Schedules of 
Assessments during the screening and treatment period is provided following the Protocol 
Synopsis. 

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8.1.1 
Screening Phase 
 
Screening procedures will be performed within 28 days of Day 1, unless otherwise specified. All 
subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any study- 
specific screening procedures are performed. After signing the ICF, completing all screening 
procedures, and being deemed eligible for entry, subjects will be enrolled in the study. Procedures 
that are performed prior to the signing of the ICF and are considered standard of care may be used 
as screening assessments if they fall within the 28-day screening window. 

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. TABLE 1: SCHEDULE OF STUDY ASSESSMENTS 
 
Assessments to be performed at the 
times stipulated in the table and as 
clinically required in the management 
of the subject. 
Screening 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 Refer to 
Section 
Window for each assessment: ±3 days, window for tumor assessment: ±7 days 
Day 
-28 to+1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Week 
-4 to +1 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Written informed 
consent/assignment of subject 
identification number 
X 
Previous treatments for prostate 
cancer 
X 
Formal verification of eligibility 
criteria 
X 
Medical and surgical history 
X 
Durvalumab and Tremelimumab 
Combination Administrationj 
X 
X 
X 
X 
Section 
6.3.1 
Durvalumab 
Administration(Mono 
therapy) 
Xj 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 
6.3.1 

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Assessments to be performed at the 
times stipulated in the table and as 
clinically required in the management 
of the subject. 
Screening 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 Refer to 
Section 
Window for each assessment: ±3 days, window for tumor assessment: ±7 days 
Day 
-28 to 
+1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Week 
-4 to+1 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (pre-, during and 
post-infusion vital signs 
assessments)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramc 
X 
As clinically indicated 
Adverse event/serious adverse 
event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 
10.1 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 
7.3 
Palliative radiotherapy 
As clinically indicated 
Section 
7.3 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry (complete 
clinical chemistry panel 
including liver enzymes)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Protocol 2016-0769 
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Assessments to be performed at the 
times stipulated in the table and as 
clinically required in the management 
of the subject. 
Screening 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 Refer to 
Section 
Window for each assessment: ±3 days, window for tumor assessment: ±7 days 
Day 
-28 to+1 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Week 
-4 to +1 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Thyroid function tests (TSH and 
T3 and fT4)e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR amd CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisf 
X 
As clinically indicated 
Coagulation parametersg 
X 
As clinically indicated 
Tumor assessment (CT or MRI); 
Bone Scan (99mTc)h 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Section 
9.0 
PSAi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 
9.3 
 
a Full physical examination at day 1 of cycle 1; targeted physical examination at other time points. Body weight recorded at all physical examinations. Height is only measured at 
screening. 
b Subjects will have their blood pressure and pulse measured before, during, and after the infusion at the following times (based on a total treatment infusion): 
• 
At the beginning of the treatment administration infusion (at ±30 minutes) 
• 
Once during treatment administration 
• 
At the end of treatment administration (±30 minutes) 
•  60 minutes post-treatment administration : (±30 minutes) –if no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation and 
vital signs period can be conducted at the Investigator’s discretion. 

Protocol 2016-0769 
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Page 48 of 103 
 
 
c ECG during screening. Thereafter as clinically indicated. Baseline and abnormal ECG at any time in triplicate others single infusion. (Clinically significant abnormalities detected 
require triplicate EKG’s). 
d If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1. Results for safety bloods must be available and reviewed 
before commencing an infusion. 
e Total T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the endocrine system. 
f Urinalysis performed at Screening, then as clinically indicated 
g Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
h CT or MRI scans will be performed every 8 weeks for the first 48 weeks and then every 12 weeks until confirmed PD. Variations, alterations, and deletions will not be 
considered deviations from the protocol. 
i Does not have to be repeated if done within 2 weeks of Cycle 1 Day 
 
j: A minimum of two combination cycles are required. Subjects experiencing adverse events (AEs) related to combination dose therapy (Part 1) that 
do not meet dose discontinuation criteria, may proceed to durvalumab monotherapy dosing (Part 2) without completing all 4 combination doses, 
Additional durvalumab monotherapy doses will be given to complete 13 treatment cycles(up to 11 durbalumab monotherapy cycles). 

Protocol 2016-0769 
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Table 2. Schedule of study procedures: follow-up for subjects who have completed durvalumab and tremelimumab treatment and achieved 
disease control (until confirmed progression of disease) and subjects who have discontinued durvalumab or tremelimumab due to toxicity 
in the absence of confirmed progression of disease 
 
Evaluation 
Time Since Last Dose of DurvalumabE 
30 days 
3 months 
12 months 
Day (±7) 
(±2 weeks) 
 Every 6 Months 
(±2 weeks) 
Physical examinationa 
X 
Vital signs (temperature, respiratory rate, blood pressure, pulse) 
X 
Weight 
X 
AE/SAE assessment 
X 
X 
Concomitant medications 
X 
X 
Palliative radiotherapy (as clinically indicated) 
World Health Organization ECOG performance status 
X 
X 
Subsequent anti-cancer therapy 
X 
X 
X 
Survival status: phone contact with subjects who refuse to return for evaluations and agree to be contacted 
Xd 
X 
Hematology 
X 
X 
Serum chemistry 
X 
X 
Thyroid function tests (TSH, and fT3 and fT4)b 
X 
ESR and CRP 
X 
Xc 
Tumour assessment (CT or MRI) 
For subjects who achieve disease control following 12 months of treatment, tumour assessments should be performed every 12 weeks relative to the date of 
first infusion thereafter until confirmed PD by RECIST 1.1 by investigational site review. Please refer to Schedule of Assessments for timings of confirmatory 
scans. 
For subjects who discontinue Durvalumab due to toxicity (or symptomatic deterioration), tumour assessments should be performed relative to the relative to the 
date of first infusion as follows: every 8 weeks for the first 48 weeks per Schedule of Assessments, then every 12 weeks until confirmed PD by RECIST 1.1 by 
investigational site review. Please refer to Schedule of Assessments for timings of confirmatory scans. 

Protocol 2016-0769 
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a Full physical exam 
b Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the endocrine system. 
 
C ESR and CRP should be collected for the first 3 follow-up visits ( Day 30, Month 3) 
d Survial status will be evaluated by phone /or in person at 30 day, 3 month and 12 month visit 
 
E If EOT is greater than 30 days after last dose, EOT will serve as 30 day visit. Subsequent follow up visits will occur at allocated time from 
EOT date and not last dose date. 

Protocol 2016-0769 
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8.1.2 
End of Treatment 
 
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. For 
subjects who discontinue durvalumab or tremelimumab prior to 12 months, end of treatment is 
considered the last visit where the decision is made to discontinue treatment. All required 
procedures may be completed within ± 7 days of the end of treatment visit. Repeat disease 
assessment is not required if performed within 28 days prior to the end of treatment visit. 
 
8.2 
Biological sampling procedures 
 
8.2.1 
Correlative studies 
 
The correlative studies will be obtained from patients participating other MD Anderson IRB 
approved biospecimen protocols. 
 
Upon treatment completion, biospecimens available will be analyzed per each approved protocol. 
In addition, new technologies have been developed.  Exosomes are vesicles secreted from cells and 
function as mediators of intercellular communication. They have been shown to play a key role in 
the cross-talk between the immune and non-immune components in the local and distant tumor 
microenvironment. Exosomes will be isolated from the plasma and bone marrow of patients, and 
molecular analyses will be performed, which will be associated with clinical outcomes. 
 
8.2.2 
Informed consent for donated biological samples 
 
Withdrawal:   
If a subject withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented. As collection of the biological samples is an integral part 
of the study, then the subject is withdrawn from further study participation. 
 
Waiver 
The additional correlative research involves reviewing medical records of patients who were treated at 
the MD Anderson Cancer Center on this trial.  The samples which will be used were previously collected 
on other laboratory trials with signed informed consent.  The trials with available samples are:  LAB02-
152, PA13-0291, PA13-0247, PA11-0852, PA12-1099, PA15-0956.  Now that patients have completed 
treatment phase it would be difficult to obtain additional informed consent. We are requesting a waiver 
of informed consent and waiver of Authorization to Use and Disclose Protected Health Information for 
the retrospective portion of this study. A Waiver of Informed Consent and a Waiver of Authorization is 
requested because the data review and sample analysis involve no additional diagnostic or therapeutic 
intervention, as well as no direct patient contact.  It would be impractical to obtain additional consent 
from patients because they are no longer in treatment, have died or may be lost to follow-up.   
 
The Principal Investigator: 
 
• Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
 
• Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 

Protocol 2016-0769 
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consent immediately and that samples are disposed/destroyed, the action documented and 
the signed document returned to the study site 
• Ensures that the subject is informed about the sample disposal. 
 
8.3 
Other assessments 
 
8.3.1 
ECOG performance status 
 
ECOG performance status will be assessed at the times specified in the assessment schedules 
() based on the following: 
0 = Fully active; able to carry on all pre-disease performance without restrictions 
1 = Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, for example, light housework or office work 
2 = Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 = Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 = Completely disabled; cannot carry on any self-care. Totally confined to bed or chair 
5 = Dead 
 
9.0 
DISEASE EVALUATION AND METHODS 
 
Imaging performed prior to informed consent may be used as baseline assessment if it was 
performed within 28 days prior to study drug administration. Scans should be scheduled in such a 
way that the scan results are available at the regularly scheduled visit. 
 
CT or MRI scans will be performed every 8 weeks for the first 48 weeks and then every 12 weeks 
until confirmed PD. 
Additional imaging may be performed at any time to confirm suspected progression of disease. 
Study films (abdominopelvic CT/MRI and bone scan) should be read on site. The principal 
investigator or a sub-investigator will evaluate the images for all subjects for the duration of the 
study. 
 
The same imaging method used for an individual subjects at baseline should be used throughout 
the entire study for that subject, unless for medical reasons the method must be changed (e.g. 
inability to receive contrast agent). 
 
If a subject is unable to return for restaging scans due to symptoms of progressive disease, he may 
have scans done by a local facility. These scans should be sent to the investigator for review. 

Protocol 2016-0769 
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PET scans should not be used to determine disease progression. 
 
Radiographic evaluation of metastatic disease is determined separately for soft -tissue and bone 
disease. 
 
9.1 
Radiographic disease assessment for soft tissue tumor deposits 
 
9.1.1 
Definition of measurable and non-measurable tumor deposits 
 
Radiographic disease assessment for soft tissue tumor deposits is based on CT or MRI scan 
imaging. Soft tissue tumor deposits are described as measurable or non-measurable as defined in 
RECIST version 1.1: 
 
• To be considered measurable, soft tissue tumor deposits (other than lymph nodes) must 
be accurately measured in at least one dimension with a minimum size of 10mm by CT or 
MRI scan (scan slice thickness no greater than 5mm). 
• To be considered pathologically enlarged and measurable a lymph node must be ≥15mm 
in short axis when assessed by CT or MRI scan (scan slice thickness no greater than 
5mm). 
• All other lesions, including small lesions (longest diameter <10mm or pathological 
lymph nodes with ≥10 to <15mm short axis) as well as truly non-measurable lesions will 
be considered non-measurable. 
 
9.1.2 
Calculation of tumor burden 
 
• At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (Σp-diam) of all index lesions (up to 5 lesions per organ, up to 
10 lesions in total that are representative of all involved organs) is calculated and 
recorded. Non-measurable tumor lesions will be recorded. 
• At each subsequent tumor assessment, the Σp-diam of the index lesions and of new, 
measurable lesions (up to 5 new lesions per organ, up to 10 lesions in total that are 
representative of all involved organs) are added together to provide the total tumor 
burden: 
o Tumor burden= Σp-diam index lesions + Σp-diam new, measurable lesions 
• Non-measurable tumor lesions should also be recorded at baseline and at each subsequent 
tumor assessment. 
• At the end of study for that subject, maximum percent reduction from baseline in tumor 
burden will be graphed 
 
9.1.3 
Definition of radiographic PD for soft tissue tumor deposits 
 
• An increase in tumor burden of ≥ 20% relative to nadir (minimum recorded tumor 
burden, including the baseline Σp-diam if that is the smallest on study). In addition to the 

Protocol 2016-0769 
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relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. 
• In patients classified as having PD within 12 weeks of last tremelimumab dose, 
confirmation of PD by a second scan ≥ 4 weeks later in the absence of rapid clinical 
deterioration will be required, as long as the patient does not show other signs or 
symptoms of disease progression as judged by the investigator. 
• The appearance of one or more new lesions (measurable or non-measurable) will not be 
considered evidence of PD as long as all of the following criteria are met: 
o The increase in tumor burden remains <20% relative to nadir. 
o There are no signs nor symptoms of disease progression (including 
laboratory parameters, e.g. worsening liver function tests attributable to 
liver metastases) as judged by the investigator. 
o There is no further increase in tumor burden observed in a repeat, 
consecutive assessment obtained ≥ 4 weeks later. 
o For non-measurable tumor lesions an increase in overall disease burden 
comparable in magnitude to the increase that would be required to declare 
PD for measurable disease (i.e. ≥20%) will be considered evidence of PD. 
o If repeat scans confirm PD, then progression should be declared using the 
date of the initial scan. 
 
9.2 
Radiographic disease assessment for bone tumor deposits 
 
Radiographic disease assessment for bone lesions is based on standard bone scintigraphy following 
technetium-99m-MDP injection. 
 
9.2.1 
Definition of radiographic PD for bone tumor deposits 
 
• Radiographic disease progression for bone lesions is defined as the appearance ≥2 new 
areas compared to the baseline bone scan that can unequivocally be attributed to prostate 
cancer (i.e. not attributable to healing or flare of pre-existing lesions). 
• Confirmation of PD by a second scan ≥4 weeks later in the absence of rapid clinical 
deterioration will be required, as long as the patient does not show other signs or 
symptoms of disease progression as judged by the investigator. 
• Equivocal progression on bone scan must be confirmed by other imaging modalities (e.g. 
CT or MRI) and/or confirmatory bone scan ≥4 weeks later. 
• If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. 
 
9.3 
PSA 
 
Samples for PSA will be collected and analyzed at the treating institution laboratory. PSA testing 
will be performed as per the schedule of assessment. The PSA test performed at the screening visit 
does not need to be repeated on C1D1 if visit occurs within 2 weeks of screening. 

Protocol 2016-0769 
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9.4 
Definition of progression of disease 
 
For the purposes of this study, progression of disease (PD) is a composite endpoint, consisting of 
clinical deterioration and/or radiographic progression as defined below. Subjects with PSA 
progression alone will not be considered to have PD. 
 
9.4.1 
Clinical deterioration 
 
Clinical deterioration is defined as any symptomatic clinical event attributable to disease 
progression that, in the investigator’s opinion, indicates that the subject is not benefiting from 
study treatment. Examples include: 
 
• Need for palliative radiation involving more than one site 
• Surgery or kyphoplasty to any neoplastic bone lesion 
• Cancer associated persistent decrease in performance status (eg, lasting for more than 14 
days) of at least 2 points from baseline 
• New bladder outlet or ureteral obstruction attributable cancer progression 
• Any change of anti-neoplastic therapy for prostate cancer 
 
9.4.2 
Radiographic progression 
 
Radiographic progression in soft tissue tumor deposits and/or bone as defined in (Sections 9.1.3 
and 9.2.1) above will be considered evidence of disease progression. 
 
PSA progression alone will not be used to define progression. 
 
10.0 ASSESSMENT OF SAFETY 
 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar 
with the content of this section. 

Protocol 2016-0769 
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Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Possible 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
Probable 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
Definitive 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
 
10.1 
Safety Parameters 
 
10.1.1 
Durvalumab + tremelimumab adverse events of special interest 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the supporter. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
 
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event that 
is associated with drug exposure and is consistent with an immune-mediated mechanism of action 
and where there is no clear alternate aetiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. 

Protocol 2016-0769 
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If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
 
AESIs observed with durvalumab and tremelimumab include: 
• Colitis 
• Pneumonitis 
• ALT/AST increases / hepatitis / hepatotoxicity 
• Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• Dermatitis 
• Nephritis 
• Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase) 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab and tremelimumab Investigator Brochure. For durvalumab and tremelimumab, 
AESIs will comprise the following: 
 
Pneumonitis 
AEs of pneumonitis are also of interest for AstraZeneca, as pneumonitis has been observed with 
use of anti-PD-1 mAbs (but not with anti-PD-L1 mAbs). Initial work-up should include a high- 
resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary consultation is highly 
recommended. Guidelines for the management of patients with immune-related AEs (irAEs) 
including pneumonitis are provided in Table 3. 
 
Infusion reactions 
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to 
AstraZeneca and are defined, for the purpose of this protocol, as all AEs occurring from the start 
of IP infusion up to 48 hours after the infusion start time. For all infusion reactions, SAEs should 
be reported to AstraZeneca Patient safety as described in Table 3. 
 
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD- 
L1 and anti-PD-1 therapy (Brahmer et al 2012). As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of mAbs can be caused by various 
mechanisms, including acute anaphylactic (IgE-mediated) and anaphylactoid reactions against the 
mAbs and serum sickness. Acute allergic reactions may occur, may be severe, and may result in 

Protocol 2016-0769 
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death. Acute allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, 
urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, 
fatigue, headache, hypertension, myalgia, vomiting, and unresponsiveness. Guidelines for the 
management of patients with hypersensitivity (including anaphylactic reaction) and infusion- 
related reactions are provided in Table 3. 
 
Hepatic function abnormalities (hepatotoxicity) 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are those 
that derive from a single blood draw or from separate blood draws taken within 8 days of each 
other. Follow-up investigations and inquiries will be initiated promptly by the investigational site 
to determine whether the findings are reproducible and/or whether there is objectiveevidence that 
clearly supports causation by a disease (eg, cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the IP. Guidelines for management of patients with hepatic 
function abnormality are provided in Table 3. 
 
Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab is 
used as monotherapy. In rare cases, colon perforation may occur that requires surgery (colectomy) 
or can lead to a fatal outcome if not properly managed. Guidelines on management of diarrhea and 
colitis in patients receiving tremelimumab are provided in Table 3. 
 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism. Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Table 3. 
 
Pancreatic disorders 
 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation. Guidelines for the management of patients with immune-mediated pancreatic disorders 
are provided in Table 3. 
 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis. Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Table 3. 
 
Nephritis 
 
Consult with Nephrologist. Monitor for signs and symptoms that may be related to changes in renal 
function (e.g. routine urinalysis, elevated serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, proteinuria, etc.) Patients should be thoroughly 
evaluated to rule out any alternative etiology (e.g., disease progression, infections etc.). Steroids 
should be considered in the absence of clear alternative etiology even for low grade events (Grade 2), 

Protocol 2016-0769 
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in order to prevent potential progression to higher grade event. Guidelines for the management of 
patients with immune-mediated neurotoxic events are provided in Table 3. 
 
10.1.2 
Immune-related adverse events 
 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation 
and proliferation, there is a possibility of observing irAEs during the conduct of this study. 
Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD- 
1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, 
dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (Hodi et al 2010, 
Brahmer et al 2012, Topalian et al 2012). These AEs are inflammatory in nature and can affect any 
organ. With anti-PD-L1 and anti-CTLA-4 combination therapy, the occurrence of overlapping or 
increasing cumulative toxicities that include irAEs could potentially occur at higher frequencies 
than with either durvalumab or tremelimumab monotherapy. Patients 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, dermatitis, 
pneumonitis, hepatitis, and endocrinopathy. In addition to the dose modification guidelines 
provided in Table 3, it is recommended that irAEs are managed according to the general treatment 
guidelines outlined for ipilimumab (Weber et al 2012). These guidelines recommend the following: 
 
• 
Patients should be evaluated to identify any alternative etiology. 
 
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature 
should be considered immune related. 
 
• 
Symptomatic and topical therapy should be considered for low-grade events. 
 
• 
Systemic corticosteroids should be considered for a persistent low-grade event or 
for a severe event. 
 
• 
More potent immunosuppressive should be considered for events not responding 
to systemic steroids (eg, infliximab or mycophenolate). 
 
• 
If the Investigator has any questions in regards to an AE being an irAE, 
the Investigator should immediately contact the Study Physician. 
Assessment of safety parameters 

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Table 3. 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non 
Immune-mediated Reactions (Durvalumab Monotherapy or Combination therapy with Tremelimumab 
  
or Tremelimumab Monotherapy) 19 August 2016 Version 
 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be madeto 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
Note: For Grade 3 and above asymptomatic amylase or lipase levels hold study 
drug/regimen and if complete work up shows no evidence of pancreatitis, may 
continue or resume study drug/regimen 
It is recommended that management of irAEs follows the guidelines presented in this 
table: 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(eg, disease progression, concomitant medications, and infections). 
− 
In the absence of a clear alternative etiology, all events should be considered 
potentially immune related. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events. 
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [eg, up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 
− 
More potent immunosuppressives such as TNF inhibitors (eg, infliximab) 
(also refer to the individual sections of the irAE for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. 
− 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(eg, inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit/risk analysis for that patient. 
 
 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; irAE Immune-related adverse event; IV intravenous; 
NCI National Cancer Institute; PO By mouth. 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
Pneumonitis/ILD 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic work- 
up for other etiologies. 
 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider pulmonary and infectious disease consult. 
 
 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (eg, prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
  
or anti-PCP treatment (refer to current NCCN guidelines for 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
Dose Modifications 
Toxicity Management 
  
version 4.03) 
 
treatment of cancer-related infections (Category 2B 
recommendation)a 
− 
Consider pulmonary and infectious disease consult. 
− 
Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life- 
threatening respiratory 
compromise; urgent 
intervention indicated 
[eg, tracheostomy or 
intubation]) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain pulmonary and infectious disease consult. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patients is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PCP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
(Category 2B recommendation).a 
 
Diarrhea/Enterocolitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes 
in bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event. 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
  
− 
Use analgesics carefully; they can mask symptoms of 
 
perforation and peritonitis. 
 
No dose modifications. 
For Grade 1: 
Grade 1 
(stool frequency of 
<4 over baseline per 
day) 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
 
Grade 2 
(stool frequency of 4 to 
6 over baseline per 
day) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can 
be resumed after completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
GI consult should be obtained for consideration of further 
workup, such as imaging and/or colonoscopy, to confirm 
colitis and rule out perforation, and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeksa. Caution: it is important to rule out bowel 
perforation and refer to infliximab label for general guidance 
before using infliximab. 
− 
Consult study physician if no resolution to Grade ≤1 in 3 to 
4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
Grade 3 or 4 
(Grade 3: stool 
frequency of ≥7 over 
baseline per day; 
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (eg infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
Hepatitis (elevated 
LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
AST or ALT > to 3 × 
ULN and/or TB > to 
1.5 × ULN) 
No dose modifications. 
• 
If it worsens, then treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
 
 
 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (eg, every 1 to 2 
days) until elevations of these are improving or resolved. 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
(AST or ALT > 3 to 
5 × ULN and/or TB 
>1.5 to 3.0 × ULN) 
• 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, discuss with study 
physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptlystart 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (mycophenolate mofetil)a Discuss with 
study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
Grade 3 or 4 
(Grade 3: AST or ALT 
>5 to 20 × ULN and/or 
TB >3.0 to 10 × ULN) 
 
 
(Grade 4: AST or ALT 
>20 × ULN and/or TB 
>10 × ULN) 
For Grade 3: 
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Perform hepatology consult, abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
Dose Modifications 
Toxicity Management 
  
version 4.03) 
 
For elevations in transaminases 
>8 × ULN or elevations in bilirubin >5 × 
ULN, discontinue study drug/study 
regimen. 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria (AST and/or ALT >3 × 
ULN + bilirubin >2 × ULN without 
initial findings of cholestasis (ie, elevated 
alkaline P04) and in the absence of any 
alternative cause.b 
 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to 
changes in renal function (eg, routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, or 
proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 
 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
  
− 
Monitor serum creatinine weekly and any accompanying 
 
(Serum creatinine > 1 
to 1.5 × baseline; > 
ULN to 1.5 × ULN) 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, 
treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
 
 
 
Grade 2 
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3 or 4 
(Grade 3: serum 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Permanently discontinue study 
drug/study regimen. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptlystart 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
 
  
creatinine 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
  
− 
Consult nephrologist and consider renal biopsy if clinically 
 
>3.0 × baseline; >3.0 
to 6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × ULN) 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED AND 
STUDY DRUG DISCONTINUED. 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
Grade 2 
 For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
− 
Consider moderate-strength topical steroid. 
 
 

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Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
• If toxicity improves to 
Grade ≤1 or baseline, 
then resume drug/study 
regimen after 
completion of steroid 
taper. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, discuss with study 
physician and promptly start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Consider skin biopsy if the event is persistent for >1 to 
2 weeks or recurs. 
 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study 
drug/study regimen. 
 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
Discuss with study physician. 
 
 
Endocrinopathy 
(eg, hyperthyroidism, 
hypothyroidism, 
hypopituitarism, and 
adrenal insufficiency) 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consult endocrinologist. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, hypotension, and weakness. 
 
 

Protocol 2016-0769 
July 28, 2020 
Page 70 of 103 
 
 
 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
Dose Modifications 
Toxicity Management 
  
version 4.03) 
 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including brain 
metastases, or infections). 
− 
Monitor and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine labs depending on 
suspected endocrinopathy. 
− 
If a patient experiences an AE that is thought to be possibly 
of autoimmune nature (eg, thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSHelevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN or consistently out of 
range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
endocrinology consult. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism, hold study drug/study 
regimen dose until patient is clinically 
stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids. 
− 
Initiate hormone replacement as needed for management. 
− 
Evaluate endocrine function, and as clinically indicated, 
consider pituitary scan. 
− 
For patients with abnormal endocrine work up, except for 
those with isolated hypothyroidism, consider short-term 
corticosteroids (eg, 1 to 2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (eg, levothyroxine, 
hydrocortisone, or sex hormones). - 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
 
 

Dose Modifications 
Toxicity Management 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Protocol 2016-0769 
July 28, 2020 
Page 71 of 103 
 
 
drug/study regimen on the following 
conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated. 
 
 
 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
For Grade 3 or 4: 
− 
Consult endocrinologist. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent 
− 
Administer hormone replacement therapy as necessary. 
− For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Once the patient is improving, gradually taper 
immunosuppressive steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for treatment of cancer- 
related infections [Category 2B recommendation]).a 
− 
Discuss with study physician. 
 
 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
General Guidance 
For Any Grade: 
− Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes, or medications). 

Dose Modifications 
Toxicity Management 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Protocol 2016-0769 
July 28, 2020 
Page 72 of 103 
 
 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain- 
Barre) 
for defining the CTC 
grade/severity) 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (eg, electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with neurological consult as 
appropriate. 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
Grade 2 
 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade 
≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade 
≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid taper. 
For Grade 2: 
− 
Discuss with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (eg, IV IG). 
 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
For Grade 3 or 4: 
− 
Discuss with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
 
 

Dose Modifications 
Toxicity Management 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Protocol 2016-0769 
July 28, 2020 
Page 73 of 103 
 
 
Permanently discontinue study 
drug/study regimen if Grade 3 irAE does 
not resolve to Grade ≤1 within 30 days. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (eg, IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
 
 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations that 
can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
that may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability. 
− 
Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological 
consult. 
− 
Neurophysiologic diagnostic testing (eg, electromyogram and 
nerve conduction investigations, and “repetitive stimulation” 
if myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best facilitated by 
means of a neurology consultation. 
 
 

Protocol 2016-0769 
July 28, 2020 
Page 74 of 103 
 
 
 
 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
Dose Modifications 
Toxicity Management 
  
version 4.03) 
 
− 
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be 
started with IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Discuss with the study physician. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult unless the symptoms are very 
minor and stable. 
 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
 
For Grade 2: 
− 
Discuss with the study physician. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider that 
steroid therapy (especially with high doses) may 
result in transient worsening of myasthenia and 
should typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. Such decisions are best made in consultation 
with a neurologist, taking into account the unique 
needs of each patient. 
 
 

Protocol 2016-0769 
July 28, 2020 
Page 75 of 103 
 
 
 
 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
Dose Modifications 
Toxicity Managemen 
  
version 4.03) 
 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
o 
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 irAE does 
not resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency or autonomic instability. 
 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Discuss with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
 
 

Protocol 2016-0769 
July 28, 2020 
Page 76 of 103 
 
 
 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
Dose Modifications 
Toxicity Management 
  
version 4.03) 
 
o Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
b 
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate 
aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE  Common Terminology Criteria for Adverse Events; ILD  Interstitial lung disease; 
irAE Immune-related adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic 
resonance imaging; NCI National Cancer Institute; NCCN National Comprehensive Cancer Network; PCP ; PO By mouth; T3 Triiodothyronine; T4 Thyroxine; TB Total 
bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 

Protocol 2016-0769 
July 28, 2020 
Page 77 of 103 
 
 
 
 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (eg, fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (eg, generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
 
 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (eg, IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
 
 
CTCAE Common Terminology Criteria for Adverse Events; IM Intramuscular; IV Intravenous; NCI National Cancer Institute. 

Protocol 2016-0769 
July 28, 2020 
Page 78 of 103 
 
 
 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (ie, events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
 
 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Grade 4 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
 
Treat accordingly, as per institutional standard. 
Treat accordingly, as per institutional standard. 
 
 
 
 
Treat accordingly, as per institutional standard. 
 
 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 

Protocol 2016-0769 
July 28, 2020 
Page 79 of 103 
 
10.2 
Assessment of relationship 
 
Adverse events will be recorded in the EMR and transferred to Prometheus using a recognized 
medical term or diagnosis that accurately reflects the event. Adverse events will be assessed by the 
investigator for severity, relationship to the investigational product, possible etiologies, and 
whether the event meets criteria of an SAE and therefore requires immediate notification to 
AstraZeneca/MedImmune Patient Safety. 
 
The following variables will be collected for each AE: 
 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IPs (yes or no) 
• 
Action taken with regard to IPs 
• 
Administration of treatment for the AE 
• 
Whether the AE caused the patient’s withdrawal from the study (yes or no) 
• 
Outcome 
In addition, the following variables will be collected for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to criteria 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to Additional Study Drug 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 

Protocol 2016-0769 
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10.3 
Study recording period and follow-up for adverse events and serious 
adverse events 
Adverse events and serious adverse events will be recorded from time of signature of informed 
consent, throughout the treatment period and including the follow-up period (90 days after the last 
dose of durvalumab + tremelimumab). 
 
During the course of the study, all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
 
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments (per Table 2), drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
assessments. 
 
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, 
even if this extends beyond study participation. 
 
Follow-up of unresolved adverse events 
 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in Prometheus. After 
90 days, only subjects with ongoing investigational product-related SAEs will continue to be 
followed for safety. 
 
AstraZeneca/MedImmune retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former studysubjects 
after the 90-day safety follow-up period for patients treated with durvalumab + tremelimumab. 
However, if an investigator learns of any SAEs, including death, at any time after the subject has 
been permanently withdrawn from study, and he/she considers there is a reasonable possibility that 
the event is related to study treatment, the investigator should notify the study sponsor and 
AstraZeneca/MedImmune Drug Safety. 

Protocol 2016-0769 
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10.4 
Reporting of Serious Adverse vents 
 
Serious Adverse Event (SAE) Reporting for MD Anderson-sponsored IND Protocols 
 
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. 
• 
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 MD 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. 

Protocol 2016-0769 
July 28, 2020 
Page 82 of 103 
 
• 
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 study 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. 
 
10.4.1 
Reporting to FDA 
 
• 
Serious adverse events will be forwarded to FDA by the IND MD Anderson (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. 
 
10.4.2 Investigator Communication with Supporting Companies 
 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is 90 days after the last dose 
of durvalumab + tremelimumab or until the initiation of alternative anticancer therapy. The 
investigator and/or Sponsor are responsible for informing the Ethics Committee and/or the 
Regulatory Authority of the SAE as per local requirements. 
 
The investigator and/or sponsor must inform the FDA, via the M.D. Anderson SAE form, of any 
serious or unexpected adverse events that occur in accordance with the reporting obligations of 21 
CFR 312.32, and will concurrently forward all such reports to AstraZeneca. A copy of the M.D. 
Anderson SAE form must be faxed to AstraZeneca at the time the event is reported to the FDA. It 
is the responsibility of the sponsor to compile all necessary information and ensure that the FDA 
receives a report according to the FDA reporting requirement timelines and to ensure that these 
reports are also submitted to AstraZeneca at the same time. 
 
* A cover page should accompany the M.D. Anderson SAE form indicating the following: 
 
• 
“Notification from an Investigator Sponsored Study” 

Protocol 2016-0769 
July 28, 2020 
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• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-15-11590) 
 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined 
by the principal investigator. 
 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com 
• 
• If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided to AstraZeneca and the FDA. 
• Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca using the MD Anderson form for serious adverse events. This 
information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly. 
 
10.4.3 
Reporting of deaths 
 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab + tremelimumab safety follow-up period must be reported as follows: 
 
• 
Death that is clearly the result of disease progression should be documented but and 
be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to as a SAE within 24 hours . The report 
should contain a comment regarding the co-involvement of progression of disease, 
if appropriate, and should assign main and contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as a SAE. 
Deaths that occur following the protocol-defined 90-day post-last-dose of Durvalumab safety 
follow-up period will be documented as events for survival analysis, but will not be reported as an 
SAE. 

Protocol 2016-0769 
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10.5 
Other events requiring reporting 
 
10.5.1 
Overdose 
 
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab in excess of 
that specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with durvalumab + tremelimumab, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox. If the 
overdose results in an AE, the AE must also be recorded as an AE (see Section 10.3). Overdose 
does not automatically make an AE serious, but if the consequences of the overdose are serious, 
for example death or hospitalization, the event is serious and must be recorded and reported as an 
SAE (see Section 10.3). There is currently no specific treatment in the event of an overdose of 
durvalumab or tremelimumab. 
 
The investigator will use clinical judgment to treat any overdose. 
 
10.5.2 
Hepatic function abnormality/Hy’s Law 
 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN may need to be 
reported as SAEs. Hepatic function abnormality (as defined in Section 10.1.3.) in a study subject, 
with or without associated clinical manifestations, is required to be reported as “hepatic function 
abnormal” 
within 
24 
hours 
of 
knowledge 
of 
the 
event 
to 
the 
sponsor 
and 
AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox (for contact 
information), unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or 
bile duct obstruction) that is unrelated to investigational product has been confirmed. 
 
• If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject 
will be based on the clinical judgment of the investigator. 
 
• If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune. 

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10.5.3 
Paternal exposure 
 
Male patients should refrain from fathering a child or donating sperm during the study and for 180 
days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the 
last dose of durvalumab monotherapy, whichever is the longer time period. 
 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented. The patient fathering the child will be asked 
to provide information. 
 
10.5.4 
Disease progression 
 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the IP is being studied. It may be an increase in the severity of the disease under 
study and/or increases in the symptoms of the disease. The development of new or progression of 
existing metastasis to the primary cancer under study should be considered as diseaseprogression 
and not an AE. Events that are unequivocally due to disease progression should not be reported as 
an AE during the study 
 
10.5.5 
New cancers 
 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the study treatment and have been 
identified after the patient’s inclusion in this study. 
 
11.0 STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
 
11.1 Description of analysis sets 
 
11.1.1 
Safety analysis set 
 
All patients who receive at least 1 dose of study drug will be included in the safety reporting and 
interim safety monitoring. 
 
11.1.2 
Efficacy analysis set 
 
To be evaluable for the secondary objectives, a patient needs to receive 2 doses of drug, have 
immune markers measured, and have at least one follow-up for clinical outcome measures. Patients 
who do not meet this level of evaluability will be described separately to establish any 

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trends in patient evaluability and comparability of compliant patients with the intended patient 
population based on available information. 
 
11.2 
Methods of statistical analyses 
 
11.2.1 
Primary safety analyses 
 
For the interim safety monitoring described below, an extreme toxicity (TOX) will be defined as 
any grade 3 or higher adverse event that is possibly, probably, or definitely related to any therapy 
received on this protocol and occurs within the first 8 weeks of therapy (2 cycles) with one 
exception. Any grade 3 or higher adverse event that is potentially treatable with steroids will only 
count as an extreme toxicity if it does not improve to grade 1 or better within 2 weeks of steroid 
therapy. 
 
At the end of the trial, all adverse events will be tabulated by their CTCAE v4.03 name, counted 
once at the worst grade and the ultimate attribution within the patient. Exploration of these 
measures by cycle may also be presented. 
 
11.2.2 
Efficacy analyses 
 
Efficacy of this combination will be measured by PSA progression-free survival (PFS), 
radiographic PFS, and maximal decline of PSA from baseline. PSA PFS, radiographic PFS, and 
time to maximal PSA decline will start at the first day of treatment and will be summarized by 
Kaplan-Meier. The numeric PSA value at maximal decline will be summarized by a boxplot and 
as a scatter plot of maximal decline by baseline PSA. 
 
11.2.3 
Biomarker endpoint analyses 
 
For continuous data, summary statistics including n, mean, standard deviation, median, minimum and 
maximum or IQR will be computed. Prostatic T cell infiltration pre-and-post biopsy will be described and 
graphed over time. Differences in either time point compared to baseline will be compared with a t-test or 
non-parametric alternative. Cox models will be implemented to explore the relationship of treatment 
combination, prostatic T cell infiltration, and progression-free survival. 
 
11.2.4 
Interim analyses 
 
Toxicity will be monitored in all patients who receive at least one dose of durvalumab + 
tremelimumab, even if the patient is not evaluable for the efficacy or biomarker endpoints. Based 
on the method of Thall et al. (1995) continual monitoring after the 6th patient is planned. 
Calculations were performed in Multc Lean 2.1. 
 
Denote the probability of TOX by Θ E. We assume Θ E ~ beta (0.8, 1.2). Our stopping rule is 
given by the following probability statement: Pr( Θ E > 0.40 | data) >0.90. That is, we will stop 

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if, at any time during the study, we determine that there is more than a 90% chance that the extreme 
toxicity rate is more than 40%, a constant rate that is the maximum acceptable for TOX. The 
stopping boundaries for this toxicity rule are to terminate if the number of TOX events compared 
to the number of patients who have received at least one dose of treatment exceeds the limits in 
this table. Continual monitoring will be carried out monthly after the 6th patient is treated 
according to the following table: 
 
Table 4. Toxicity monitoring rules (after the 6 patient is treated) 
 
If there are this many patients with TOX: 
5 
6 
7 
8 
9 
10 
11 12 
13 
14 
Stop if there are this many or fewer 
patients treated with ≥1 dose of study drug: 
7 
9 
11 
13 
15 
17 
20 22 
24 
26 
 
If the trial enrolls 27 patients, the trial will stop there regardless of the number of patients with 
TOX. However, the trial may stop between 20 and 27 patients once 20 evaluable patients are 
enrolled unless the trial stops for toxicity first. This means the probability of stopping early is over- 
estimated in the operating characteristics below since the trial may stop for evaluability after 24 
patients are enrolled. In this case, the probability of stopping for TOX is overestimated by the 
probability of stopping at 25 or 26 patients. Similarly, the median, 25th, and 75th percentile of the 
sample sizes may be slightly overestimated. 

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Table 5. Operating Characteristics for the Toxicity Monitoring Rule assuming all 27 patients 
are enrolled 
 
True 
TOX 
rate 
Probability 
of Stopping 
Early 
Probability of 
Enrolling ≥ 20 
Patients 
Average 
Number of 
Patients 
Average 
Number of 
Patients 
with TOX 
Median 
(25th %ile, 75th %ile) 
25 
0.02 
0.98 
26.6 
6.6 
27 (27, 27) 
30 
0.06 
0.95 
26.0 
7.8 
27 (27, 27) 
35 
0.13 
0.89 
25.0 
8.7 
27 (27, 27) 
40 
0.25 
0.80 
23.3 
9.3 
27 (27, 27) 
45 
0.41 
0.67 
21.0 
9.5 
27 (13, 27) 
50 
0.59 
0.53 
18.3 
9.2 
20 (11, 27) 
55 
0.75 
0.47 
15.5 
8.5 
13 (7, 26) 
 
MDACC Investigational New Drug (IND) office will review Efficacy/Toxicity data with 
Principal Investigator (and statistician if needed) at a predetermined interval as indicated next: 
The first analysis will occur after the first 6 subjects are treated for at least 2 cycles, and reports 
submission will continue in cohort size of 2 subjects, thereafter. On every report submission, the 
information from previous reported patients will need to be updated. 
 
 
11.3 
Determination of sample size 
 
The selection of 20 evaluable patients was intended as a pilot sample size with sufficient numbers 
to establish safety in this population as shown in Table 5 above while providing sufficient numbers 
for the secondary endpoints. This will allow investigation of a few marker endpoints and establish 
safety and feasibility of measuring the markers of interest while being able to accrue within 6 
months. No formal hypotheses are planned. These patients will form the basis of designing a 
hypothesis-driven study in the future. However, we can make a statement about what might be 
detected in secondary endpoints at this sample size. The association between CD3 change and PSA 
PFS will be explored with a Cox model with CD3 as a continuous measure. Assuming that 

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75% (80%) of patients will progress by the end of the study, 20 patients will have 80% power to 
detect a regression coefficient of 0.72 (0.70) at a 2-sided 5% significance level, assuming the 
change in CD3 has a standard deviation of 1. The regression coefficient of 0.72 (0.70) is equivalent 
to a hazard ratio of 2.1 (2.0) or a doubling of risk per unit increase in CD3 (Calculations performed 
in NCSS-PASS 2005). This would hold true for both biomarker and any model of PSA PFS or 
Radiological/Clinical PFS. 
 
Even if fewer than 20 patients have information available, this is the first look at these measures. 
Therefore, the descriptive information gathered on biological markers and outcomes, as well as 
the feasibility of collecting such information in future trials will be valuable. 
 
12.0 STUDY MANAGEMENT 
 
12.1 
Monitoring of the study 
 
This study will be monitored for compliance by the IND Office. 
 
12.2 
Study Completion/End of Study 
 
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the clinical trial agreement. 
 
12.3 
Records and Reports 
 
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation (e.g. case report form) on 
each individual treated. The investigator is required to retain, in a confidential manner, the data 
pertinent to the study. Prometheus will be used as the electronic case report form for this study. 
All protocol specific data, including adverse events, will be entered into Prometheus. This study 
will be monitored for compliance by the IND Office. 
 
12.4 
Privacy of Personal Data 
 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. 
 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 

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put in place. Personnel whose responsibilities require access to personal data agree to keep the 
identity of subjects confidential. 
 
Data will be entered into MD Anderson institutionally approved and compliant database(s). The 
database(s) have secure portal that requires users to login with validated credentials, uses 
approved encryption protocols as defined by institutional information security standards. 
 
Systems have granular data access controls to ensure that the minimal amount of information 
required to complete a task is presented, can handle de-linking and de-identification of patient 
information to maintain patient confidentiality if necessary. The system(s) are 21 CFR 11 
compliant. Standard data collection, storage procedures, and quality assurance procedures will be 
followed, to ensure integrity and auditability of all information entered. 
All patients will be registered in the University of Texas MD Anderson Cancer Center Office of 
Research Administration database. Registration will occur following informed consent process 
and prior to initiation of investigational intervention(s). All eligibility criteria must be satisfied. 
 
12.5 
Record Retention 
 
The Investigator must retain study drug disposition records, source documents, and case histories 
designed to record all observations and other data pertinent to the investigation (e.g. case report 
form) for the maximum period required by applicable regulations and guidelines, or Institution 
procedures. 
If the Investigator withdraws from the study (e.g. relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g. another Investigator, IRB). Documentation of 
such transfer must be provided to MedImmune. 

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APPENDIX 1. 
ACTIONS REQUIRED IN CASES OF INCREASES IN 
LIVER BIOCHEMISTRY AND EVALUATION OF HY’S LAW 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law. It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. Specific guidance on the managing liver abnormalities can be 
found in Section  
and  
of the protocol. 
 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
 
Definitions 
 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 × Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication, irrespective of an increase in Alkaline Phosphatase 
(ALP). 
 
Hy’s Law (HL) 
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
 
For PHL and HL, the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations 
in transaminases and TBL must occur. 
 
Identification of Potential Hy’s Law Cases 

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In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in isolation 
or in combination: 
 
• 
ALT ≥3 × ULN 
• 
TBL ≥2 × ULN 
The Investigator will without delay review each new laboratory report, and if the identification 
criteria are met will: 
 
• 
Determine whether the patient meets PHL criteria (see Section Definitions of this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
 
• 
Promptly enter the laboratory data into the laboratory eCRF 
Follow-up 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
 
• 
Notify the AstraZeneca representative who will then inform the central Study Team. 
The Study Physician contacts the Investigator, to provide guidance, discuss, and agree on an 
approach for the study patient’s follow-up and the continuous review of data. Subsequent to this 
contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. 
 
• 
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. 
 
• 
Complete the 3 Liver eCRF Modules as information becomes available. 
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 

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Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
 
• 
No later than 3 weeks after the biochemistry abnormality was initially detected, the 
Study Physician contacts the Investigator in order to review available data and agree 
on whether there is an alternative explanation for meeting PHL criteria other than DILI 
caused by the 
 
IMP. The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF 
accordingly and follow the AZ standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
 
• 
Report an SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes. 
 
− 
The “Medically Important” serious criterion should be used if no other serious 
criteria apply. 
 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned. 
 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
 
• 
Report an SAE (report term “Potential Hy’s Law”), applying serious criteria and 
causality assessment as per above. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review. 

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Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment 
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment, having previously met PHL criteria at a study visit prior to starting study treatment. 
 
At the first on study treatment occurrence of PHL criteria being met the Investigator will: 
 
• 
Determine if there has been a significant change in the patients’ condition# compared 
with the last visit where PHL criteria were met# 
− 
If there is no significant change no action is required. 
− 
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described is 
Section Potential Hy’s Law Criteria metof this Appendix. 
#A “significant” change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Study Physician if there is any uncertainty. 
 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit. 
 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study, eg, chronic or progressing malignant disease, severe infection, 
or liver disease, or did the patient meet PHL criteria prior to starting study treatment and 
at his or her first on-study treatment visit as described in Section Actions Required When 
Potential Hy’s Law Criteria are Met Before and After Starting Study Treatment? 
If No: follow the process described in Section Potential Hy’s Law Criteria metof this Appendix. 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with when 
PHL criteria were previously met 
• 
If there is no significant change, no action is required. 

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• 
If there is a significant change, follow the process described in Section Potential Hy’s 
Law Criteria met of this Appendix. 
#A “significant” change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Study Physician if there is any uncertainty. 
 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’: 
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U 
CM174090.pdf 

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APPENDIX 2. 
DURVALUMAB DOSE CALCULATIONS 
 
For durvalumab dosing done depending on subject weight: 
 
1. Cohort dose: X mg/kg 
 
2. Subject weight: Y kg 
 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
 
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 50 (mg/mL) 
Where 50 mg/mL is durvalumab nominal concentration. 
 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). 
Dose adjustments for each cycle are only needed for greater than 10% change in weight. 
 
5. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula: 
 
Number of vials = Dose (mL) / 10.0 (mL/vial) 
 
Example: 
 
1. Cohort dose: 10 mg/kg 
 
2. Subject weight: 30 kg 
 
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
 
4. Dose to be added into infusion bag: 
 
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
 
5. The theoretical number of vials required for dose preparation: 
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials 

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Appendix 3. 
DURVALUMAB DOSE VOLUME CALCULATIONS 
 
For durvalumab flat dosing: 
 
1. Cohort dose: X g 
 
2. Dose to be added into infusion bag: 
Dose (mL) = X g × 1000 / 50 (mg/mL) 
Where 50 mg/mL is durvalumab nominal concentration. 
 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). 
 
3. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula: 
 
Number of vials = Dose (mL) / 10.0 (mL/vial) 
 
Example: 
 
1. Cohort dose: 1.5 g 
 
2. Dose to be added into infusion bag: 
 
Dose (mL) = 1.5 g ×1000 / 50 (mg/mL) = 30.0 mL 
 
3. The theoretical number of vials required for dose preparation: 
Number of vials = 30.0 (mL) / 10.0 (mL/vial) = 3 vials 

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APPENDIX 4. 
TREMELIMUMAB DOSE CALCULATIONS 
 
For tremelimumab dosing done depending on subject weight: 
 
1. Cohort dose: X mg/kg 
 
2. Subject weight: Y kg 
 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
 
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 20 (mg/mL) 
Where 20 mg/mL is tremelimumab nominal concentration. 
 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 
mL). Dose adjustments for each cycle are only needed for greater than 10% change in weight. 
 
5. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula: 
 
Number of vials = Dose (mL) / 20.0 (mL/vial) 
 
Example: 
 
1. Cohort dose: 1 mg/kg 
 
2. Subject weight: 30 kg 
 
3. Dose for subject: 30 mg = 1 (mg/kg) × 30 (kg) 
 
4. Dose to be added into infusion bag: 
 
Dose (mL) = 30 mg / 20 (mg/mL) = 1.5 mL 
 
5. The theoretical number of vials required for dose preparation: 
Number of vials = 1.5 (mL) / 20.0 (mL/vial) = 1 vials 

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APPENDIX 5. 
TREMELIMUMAB DOSE VOLUME CALCULATIONS 
 
For tremelimumab flat dosing: 
 
1. Cohort dose: X mg 
 
2. Dose to be added into infusion bag: 
Dose (mL) = X mg / 20 (mg/mL) 
Where 20 mg/mL is tremelimumab nominal concentration 
 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 
mL). 
 
3. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula: 
 
Number of vials = Dose (mL) / 20 (mL/vial) 
 
Example: 
 
1. Cohort dose: 75 mg 
 
2. Dose to be added into infusion bag: 
 
Dose (mL) = 75 mg / 20 (mg/mL) = 3.8 mL 
 
3. The theoretical number of vials required for dose preparation: 
Number of vials = 3.8 (mL) / 20 (mL/vial) = 1 vial 
The footnotes below need to be placed below the toxicity management guidelines -