Clinical trial NCT03015129
Conditions: Endometrial Cancer Endometrial Carcinosarcoma Endometrial Carcinoma Endometrial Cancer Recurrent Endometrial Carcinoma, Recurrent
Keywords: Durvalumab MEDI4736 Tremelimumab anti-PD-L1 Antibody anti-CTLA-4 antibody 16-1491
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2017-01-01; Completion date: 2022-12-30
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will test the safety and efficacy of the experimental drug called durvalumab with or without another experimental drug called tremelimumab in endometrial cancer.

Radiologic tumor assessment will be repeated every 8 weeks +/- 7 days for the first 48 weeks and then every 12 weeks +/- 7 days until PD. For patients who remain progression free 2 years post completion of protocol directed treatment, every 6 months +/- 1 month. irRECIST assessments will only be completed for patients continuing treatment beyond PD.

Detailed description:

Arms: arm 1: Patients will receive intravenous infusion of durvalumab 1500mg Fixed Dose every 4 weeks until patient develops a loss of clinical benefit or experiences unacceptable toxicities. arm 2: Patients will receive 1500mg Flat Dose durvalubmab via intravenous infusion every 4 weeks for up to 4 cycles and 75mg tremelimumab via intravenous infusion every 4 weeks for up to 4 cycles, and then continue 1500mg Fixed Dose durvalumab every 4 weeks until patient develops a loss of clinical benefit or experiences unacceptable toxicities.
Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1491 A(17) 
Approval date: 05-Jan-2022 
 
 
 
 
MSK PROTOCOL COVER SHEET 
 
 
A Phase 2 Trial of Durvalumab [MEDI4736](anti-PD-L1 Antibody) with or without 
Tremelimumab (anti-CTLA-4 antibody) in Patients with Persistent or Recurrent 
Endometrial Carcinoma and Endometrial Carcinosarcoma 
 
 
Principal  Investigator/Department: 
Vicky Makker, MD / Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
Page 1 of 98 


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 21 
4.1 Design ................................................................................................................................ 21 
4.2 Intervention .............................................................................................................................. 21 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 22 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 28 
6.1 Subject Inclusion Criteria .................................................................................................... 28 
6.2 Subject Exclusion Criteria ................................................................................................... 29 
7.0 
RECRUITMENT PLAN ................................................................................................................... 31 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 32 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 32 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 34 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 37 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 68 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 76 
14.0 
BIOSTATISTICS ............................................................................................................... 77 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES81 
15.1 Research Participant Registration ......................................................................................... 81 
15.2 
Randomization ................................................................................................................... 81 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 81 
16.1 
Quality Assurance ........................................................................................................ 82 
16.2 
Data and Safety Monitoring .............................................................................................. 83 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 83 
17.1 
Privacy .......................................................................................................................... 83 
17.2 Serious Adverse Event (SAE)  Report…………………………………………………………..83 
18.0 
Informed  Consent Procedures ………….…………………………………………………….87 
19.0 
REFERENCES ...................................................................................................................... 89 
20.0 
APPENDICES ................................................................................................................... 95 


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Appendix A Schedule of study procedures: follow-up for subjects who have completed 
durvalumab and tremelimumab and achieved disease control (until progression of 
disease) and subjects who have discontinued durvalumab or tremelimumab due to 
toxicity in the absence of progression of disease 
 
Appendix B Durvalumab DOSE Volume  CALCULATIONS 
Appendix C Tremelimumab DOSE VOLUME CALCULATIONS 
Appendix D Biomarkers 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
A Phase 2 Trial of Durvalumab [MEDI4736] (anti-PD-L1 Antibody) with or without 
Tremelimumab (anti-CTLA-4 antibody) in Patients with Persistent or Recurrent Endometrial 
Carcinoma and Endometrial Carcinosarcoma. 
This is a prospective, randomized, phase 2 study which will assess the efficacy and safety of 
a single agent versus combination immune checkpoint inhibition for patients with persistent 
or recurrent endometrial carcinoma or endometrial carcinosarcoma.  Eighty women with 
persistent or recurrent endometrial carcinoma or endometrial carcinosarcoma , who have  
had at least one prior platinum chemotherapy regimen and have progressed will be eligible 
for treatment if they have measurable disease and adequate organ function. Approximately 
40 patients will be randomized to treatment on one of two arms: Durvalumab alone or 
Durvalumab in combination with Tremelimumab. Patients with clinically significant 
autoimmune disease will be excluded. Durvalumab would be administered intravenously (IV) 
every 4 weeks until unacceptable toxicity or progression of disease (whichever occurs first 
(and Tremelimumab would be administered intravenously (IV) every 4 weeks for up to 4 
cycles or until unacceptable toxicity or progression of disease (whichever occurs first). 
Treatment cycles will be 28 days. 
 
Primary Endpoints 
 
• 
Determine the effectiveness of the each arm by measuring Overall Response Rate 
[ORR = Complete Response (CR) + Partial Response (PR)] by RECIST v 1.1 
• 
Determine Progression Free Survival (PFS) rate in each arm at 24 weeks (+/- 1 
week) 
Secondary Endpoints. 
 
• 
Overall response rate in each arm evaluated by Immune-related Response Criteria in 
Solid Tumors (irRECIST) criteria. irRECIST assessments will only be completed for 
patients continuing treatment beyond PD. 
• 
Clinical benefit (CR + PR + Stable Disease [SD]) rate in each arm by 24 weeks +/- 7 
days Duration of response in each arm 
• 
Determine the rate of immune-related  Adverse Events (irAE) 
• 
Determine the rate of serious adverse events (SAE) 
• 
Establish safety of each arm 


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Exploratory Endpoints 
 
• 
Determine the ability of the laboratory parameters to predict clinical benefit: 
o Archival tumor tissue PD-L1 expression IHC 
o Archival tumor tissue immune-related gene expression profiles 
o Archival tumor tissue IHC 
o Peripheral blood immune phenotyping 
o Peripheral blood gene expression profiling 
o Peripheral blood T cell receptor repertoire 
o Peripheral blood serologic responses 
Patient Population: 
 
• 
Sample size: 80 patients; 40 patients in each arm 
• 
Patients with recurrent or persistent endometrial carcinoma or carcinosarcoma, which 
is refractory to curative therapy or established treatments. 
• 
Patients whose disease has progressed following completion of at least one prior 
platinum regimen with the following histologic epithelial cell types are eligible: 
o Endometrioid  adenocarcinoma 
o Serous adenocarcinoma 
o Undifferentiated  carcinoma 
o Mixed epithelial carcinoma 
o Adenocarcinoma not otherwise specified (N.O.S.) 
o Carcinosarcoma 
• 
Adequate organ function and performance status ECOG 0-1 
• 
At least 1 target lesion, which is measurable by RECIST and was not previously 
irradiated 
• 
Expression of PD-L1 will be assessed from stored tissue samples, but not required for 
eligibility 
Treatment Plan: 
 
Arm 1: Patients will receive intravenous (IV) infusion of durvalumab 1500mg Fixed Dose 
every 4 weeks until patient develops a loss of clinical benefit or experiences unacceptable 
toxicities. 
Arm 2:  Patients will receive durvalumab + tremelimumab combination therapy. Patients will 
receive 1500 mg Fixed Dose durvalumab via IV infusion q4w for up to 4 cycles and 75 mg 
tremelimumab via IV infusion q4w for up to 4 cycles, and then continue 1500 mg Fixed Dose 
durvalumab every 4 weeks until patient develops a loss of clinical benefit or experiences 
unacceptable toxicities. 
Radiologic tumor assessment will be repeated every 8 weeks +/- 7 days for the first 48 
weeks and then every 12 weeks +/- 7 days until PD. For patients who remain progression 
free 2 years post completion of protocol directed treatment, every 6 months +/- 1 month. 
Treatment will continue until progression, intolerance, withdrawal, study completion, or study 


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termination. It is estimated that full accrual will be achieved within 24 months; 3 years is 
estimated between time of opening and time of last treatment. 
 
 
 
 
Patients will be randomized to either: 
 
• 
Arm 1: durvalumab (anti-PD-L1 Antibody) alone, or 
• 
Arm 2: durvalumab with tremelimumab (anti-CTLA-4 antibody) 
 
Patients will be stratified by histology, and we will limit enrollment of stratum 1 to 10 patients 
per arm. 
• 
Stratum 1: endometrial carcinosarcoma patients OR MSI-high  endometrial carcinoma 
patients 
• 
Stratum 2: other histologies 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Endpoints: 
 
• 
Determine the effectiveness of the each arm by measuring Overall Response Rate 
[ORR = Complete Response (CR) + Partial Response (PR)] by RECIST v 1.1 
• 
Determine Progression Free Survival (PFS) rate in each arm at 24 weeks (+/- 1 
week) 
• 
Secondary Endpoints 
 
• 
Overall response rate in each arm evaluated by Immune-related Response Criteria in 
Solid Tumors ( irRECIST) criteria. irRECIST assessments will only be completed for 
patients continuing treatment beyond PD 
• 
Clinical benefit (CR + PR + Stable Disease [SD]) rate in each arm by 24 weeks +/- 7 
days Duration of response in each arm 
• 
Determine the rate of immune-related  Adverse Events (irAE) 
• 
Determine the rate of serious adverse events (SAE) 
• 
Establish safety of each arm 
 
Exploratory Endpoints: 
 
• 
Determine the ability of the laboratory parameters to predict clinical benefit: 
o Archival tumor tissue PD-L1 expression IHC 
o Archival tumor tissue immune-related gene expression profiles 
o Archival tumor tissue IHC 
o Peripheral blood immune phenotyping 
o Peripheral blood gene expression profiling 
o Peripheral blood T cell receptor repertoire 


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o Peripheral blood serologic responses 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Introduction 
 
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 (Krambeck et al, 2007), pancreatic (Loos et al, 2008), 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 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 (Nakano et al, 2001; 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 
suchas 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, 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). 
 
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 


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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-cellinfiltration 
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 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). 
 
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. Studies in 
mousemodels of transplantable tumors have demonstrated that manipulation of co-stimulatory 
or co-inhibitory signals can amplify T-cell responses against tumors. 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]). 
Immunotherapy with checkpoint inhibition is improving long-term disease control for patients 
with diverse malignancies (Topalian 2012; Hamid 2013; Wolchok 2013; Powles 2014), 
including patients with ovarian cancer (OC) (Hodi 2008; Brahmer 2012). The primary 
mediators of adaptive immune blockade, whose targeting in clinical trials have yielded 
results, include CTLA-4 (Hodi 2010; Ribas 2013), PD-1 (Topalian 2012; Hamid 2013; Robert 
2014), and PD-L1 (Brahmer 2012). Responses in tumors such as melanoma, non-small cell 
lung cancer, and renal cell cancer have been impressive. 
Durvalumab (MEDI4736): anti-PD-L1 Monoclonal Antibody. 
 
The non-clinical and clinical experience is fully described in the current version of the 
durvalumab Investigator’s Brochure (IB Version 9.0). 
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. 


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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. 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 tumor models support this hypothesis, 
where antibodies directed against PD-L1 or its receptor PD-1 showed anti-tumor activity. 
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 18Sep2015, durvalumab IB 
version 9.0), a total of 1,910 subjects have been enrolled and treated in 30 ongoing 
durvalumab clinical studies, including 20 sponsored and 10 collaborative studies. Of the 1,910 
subjects, 1,279 received durvalumab monotherapy, 454 received durvalumab in combination 
with tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 13 
MEDI6383), and 163 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 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. 
 
Tremelimumab: Anti-CTLA-4  Monoclonal  antibody 
 
The non-clinical and clinical experience is fully described in the current version of the 
tremelimumab Investigator’s  Brochure (IB Version 6.0). 


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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. 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 5.0, 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 (1 
November 2015 for monotherapy studies and 15 April 2015 to 12 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 completed and 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 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 tumor types have received tremelimumab in combination with 
other anticancer agents. Refer to the current tremelimumab IB for a complete summary of 
non-clinical and clinical information; see Section 11.0 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. 
 
Durvalumab in combination with tremelimumab 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity 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 


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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 102 patients have been treated, and 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 associationbetween 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 agents. 
 
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. 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. 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.  Similar results have been 


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observed in an ongoing study of durvalumab + tremelimumab in NSCLC, with further updated 
details presented in this clinical study protocol. 
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. 
 
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were 
narrowed to 15 and 20 mg/kg durvalumab q4w. PK simulations from the 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 durvalumab. The observed durvalumab PK data from the D4190C00006 study 
were well in line with the predicted monotherapy PK data developed preclinically. 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 Cmax at steady state (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 monotherapy with combination 
doses containing 1 mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab 
plus 1 mg/kg tremelimumab combinations. 
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 
and colitis, were more commonly seen in cohorts using either 3 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 


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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 11 patients  treated in  the 
20 mg/kg durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥3 AEs, 
SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical 
activity. This cohort had a lower number of treatment related Grade ≥3 AEs or treatment 
related SAEs.  No dose-limiting toxicities were reported. 
 
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. 
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity  to other  dose  combinations.  A  total  of  5 of 
11 patients in the 20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for 
efficacy with at least 8 weeks of follow-up. Of these, there were 2 patients (40%) with partial 
response (PR), 1 patient (20%) with stable disease (SD), and 1 patient (20%) with progressive 
disease (PD). The fifth patient had only a single scan, which was conducted outside the 
window for these evaluations. 
 
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still 
showed some evidence of clinical activity.  All together, the data suggested that a 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab dose combination should be selected for further 
development. 
 
Long term data 
 
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. 
 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 
 
o 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 


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(doses 1 and 10 mg/kg) at the time of data analysis. 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. 
 
o 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 
 
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. 
Immune checkpoint Inhibition in endometrial carcinomas 
 
Endometrial carcinomas encompass several different histologies, which include 
endometrioid, serous, clear cell, and carcinosarcoma.  Endometrial cancer is the second 
leading cause of death from gynecologic cancer with an estimated 8,590 women dying in the 
United Stated annually (Seigel et al, 2014)). Carboplatin and paclitaxel is the standard first 
line treatment regimen (Miller et al, 2012) for advanced recurrent or persistent disease, but 
unfortunately, there are no FDA approved treatments for patients who progress on first line 
therapy with the exception of Megace as a palliative treatment for advanced endometrial 
carcinomas. As a result, there is tremendous opportunity for the development of rationally 
therapeutic agents in the recurrent/persistent endometrial cancer space. Specifically, 
strategies reversing tumor promoting processes involving the interaction between tumor- 
infiltrating T-cells and the host microenvironment would be tremendously worthwhile, 
especially in genetically unstable tumors. 
While patients with endometrial cancer have not been included in the initial studies using 
immune checkpoint inhibitors, there is a high rationale for such studies. Multiple studies have 
investigated the tumor microenvironment in different subtypes of endometrial cancer. 
Similarly to other tumor types, tumor-infiltrating CD8 T lymphocytes have been demonstrated 
to carry positive prognostic implications for patients with endometrial cancer (Kondratiev, 
2004), while hypermutated genotypes are associated with increased numbers of tumor- 
infiltrating lymphocytes and PD-L1 expression (Howitt, 2015), as discussed below. 
Early work in endometrial cancer has shown that the majority of tumor infiltrating  
lymphocytes (TILs) in endometrial carcinomas express the CD8+ suppressor/cytotoxic 
phenotype, and minor subsets express B-lymphocyte and macrophage markers.  The 
earliest evidence demonstrating that increased numbers of CD8+ T lymphocytes (CTLs) 
were associated with survival came from immunohistochemical staining CD8(+) T cells in the 
following four regions: lymphocytes infiltrating the tumor epithelium at the invasive border, 
within the underlying tumor stroma, within the superficial tumor epithelium, and in the 
perivascular areas of the myometrium in endometrial carcinoma patients. Results showed 
that patients with >10 CD8(+) T lymphocytes/high-power field within the tumor epithelium at 
the invasive border displayed improved overall survival compared with patients with fewer 
intraepithelial CD8(+) T lymphocytes (87 and 50%, respectively; P = 0.027). Multivariate 
analysis revealed that stage, vascular invasion, grade, and the number of intraepithelial 


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CD8(+) T lymphocytes at the invasive border were the only independent predictors of  
survival (P < 0.0001, P = 0.001, P = 0.011, and P = 0.025, respectively). Granzyme B(+) 
cytoplasmatic granules were detected in a high proportion of CTLs, confirming their activated 
cytotoxic phenotype. (Kondratiev, 2004) 
Immunohistochemistry on tissue microarrays containing tumor from 368 FIGO stage I-IV 
endometrial cancer patients revealed that high numbers of intra-tumoral CD8(+) T- 
lymphocytes, a high CD8(+)/FoxP3(+) ratio and the presence of CD45R0(+) T-lymphocytes 
were strongly associated with well-known favorable prognostic factors in endometrial cancer. 
Furthermore, high numbers of CD8(+) T-lymphocytes and a high CD8(+)/FoxP3(+) ratio were 
associated with a better disease free survival (DFS). In multivariate analysis, high numbers  
of CD8(+) T-lymphocytes had an independent prognostic impact for overall survival in the 
entire cohort (HR 0.48, 95% C.I. 0.26-0.89, p=0.019) and in type II endometrial cancer (HR 
0.17, 95% C.I. 0.08-0.36, p<0.001). A high CD8(+)/FoxP3(+) ratio was independently 
associated with improved survival in type I endometrial cancer (HR 0.44, 95% C.I. 0.23-0.84, 
p=0.013). CD45R0(+) lymphocytes were an independent factor for improved OS (HR 0.42, 
95% C.I. 0.19-0.93, p=0.033). (de Jong, 2009) 
The Cancer Genome Atlas (TCGA) recently reported on the genomic, transcriptomic, and 
proteomic analysis of 373 endometrial carcinomas using massively parallel sequencing and 
array-based technologies, in combination with DNA methylation, reverse-phase protein array, 
and microsatellite instability analyses.(Kandoth, 2013) Based on the integration of the  
somatic gene mutations, microsatellite instability, and somatic copy-number alterations 
results, endometrial carcinomas were categorized into four genomic groups: (1) A group of 
‘ultramutated’ tumors characterized by very high mutation rates, all harboring mutations in 
the exonuclease domain of the polymerase epsilon (POLE) gene; (2) A ‘hypermutated’ group 
of endometrial carcinomas characterized by microsatellite instability due to MLH1 promoter 
methylation, with high mutation rates and few copy-number alterations; (3) A ‘copynumber 
low’ group comprised of most of the microsatellite stable grade 1 and grade 2 endometrioid 
carcinomas with low mutation rates; and (4) A group of ‘copy-number high’ tumors with 
extensive copy number aberrations, low mutation rates, and recurrent TP53 mutations 
comprised of serous carcinomas and 25% of FIGO (International Federation of Gynecology 
and Obstetrics) grade 3 endometrioid adenocarcinomas. With regards to clinical outcome, 
ultramutated endometrial carcinomas with POLE exonuclease domain mutations had a 
favorable progression free survival as compared with the other three TCGA genomic groups. 
(Kandoth, 2013) It has been suggested that hypermutated tumors may harbor more tumor 
specific neoantigens and increased amounts of TILs. Therefore, an assessment of whether 
POLE and MSI ECs harbor more neoantigens and TILs than the comparatively hypomutated 
microsatellite-stable (MSS) ECs was performed. Prediction of neoantigen load was 
performed using sequencing data from the Cancer Genome Atlas data set. Evaluation of 
tumor-infiltrating lymphocytes (TILs) and PD-1 and PD-L1 expression was performed in 63 
patients with EC referred to our institution. The predicted median (range) neoantigen load 
(predicted neoepitopes per sample) was proportional to the mutational load: highest in 
ultramutated polymerase e (POLE) tumors (8342 [628-20 440]), less in hypermutated MSI 
(541 [146-8063]; P < .001), and lowest in microsatellite-stable tumors (70.5 [7-1877]; 
P < .001). The POLE and MSI ECs exhibited higher numbers of CD3+ (44.5 vs 21.8; 
P = .001) and CD8+ (32.8 vs 13.5; P < .001) TILs compared with microsatellite-stable tumors. 


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PD-1 was overexpressed in TILs (81% vs 28%; P < .001) and peritumoral lymphocytes (90% 
vs 28%; P < .001) of POLE and MSI tumors. PD-L1 expression was infrequently noted in 
tumor cells but was common in intraepithelial immune cells and more frequent in POLE and 
MSI tumors (39% vs 13%; P = .02). (Howitt, 2015) 
Taken together, we believe that this data provides abundant rationale to investigate the 
efficacy of the anti-PD-L1 agent durvalumab with or without the anti-CTLA4 agent 
tremelimumab in patients with advanced/recurrent endometrial malignancies.  At this time, 
there is tremendous interest in evaluating immune check-point inhibitors in advanced 
endometrial cancers. 
Rationale for combining Durvalumab and Tremelimumab in Endometrial Carcinomas 
 
There is sound rationale for evaluating the combination of durvalumab and tremelimumab for 
the treatment of advanced endometrial carcinomas. Firstly, the mechanisms of activation of 
known sites for activity of CTLA-4 and PD-1 are non-redundant, suggesting that targeting 
both pathways may have additive or synergistic activity. Secondly, preclinical data in mouse 
models of transplantable solid tumors, and clinical data emerging from studies in melanoma 
supports the superior anti-tumor activity of combination therapy over monotherapy, albeit at 
increased toxicity (Larkin, 2015 #9006). Based upon these observations, combination 
therapy may generate superior anti-tumor activity, which may translate into higher rates of 
response in tumors. However, as yet, it is not known whether combination therapy will result 
in superior activity in comparison to single agent durvalumab in endometrial cancer and 
whether the combination will be safe in this patient population. 
For this study, we hypothesize that durvalumab plus tremelimumab will be well tolerated and 
will be associated with higher efficacy than the durvalumab alone in patients with advanced 
endometrial cancer and endometrial carcinosarcoma. 
 
 
Efficacy Data 
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 solid tumors. 
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 


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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). 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 12.6 months in this first 
line setting as compared to 10.71 months with standard chemotherapy; however, these results 
were not statistically significant. 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). 
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, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may 
have profound and durable benefits in patients with melanoma. 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 assayhas 
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 (e.g., NSCLC, renal cell carcinoma, 
and melanoma), that monotherapy may be more efficacious (in terms of ORR) in patients who 
are PD-L1-positive. 


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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. 
Potential risks 
Potential risks, based on the mechanism of action of durvalumab and related molecules, 
include immune-mediated reactions, such as colitis, pneumonitis, hepatitis/hepatotoxicity, 
neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, pancreatitis and nephritis. 
Additional important potential risks include infusion related reactions, hypersensitivity, 
anaphylaxis  or serious allergic reactions, serious infections, and immune complex disease. 
 
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 


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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 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 discontinuation of 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
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; respiratory 
tract 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 1 November 2015 (for all studies except D4190C00006 that has 
a cutoff date  of 15Apr2015 and  not including 497  patients who have  been treated  in the 


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ongoing blinded Phase IIb Study D4880C00003) experienced at least 1 AE. The events that 
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. 
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 subjects), and 
increased AST (2 subjects). Additional safety results from this study are presented in the 
durvalumab and tremelimumab IBs. 
 
In the literature, using the combination of the same class of drugs (e.g., 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 


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noted in 72% of patients, with Grade 3 or 4 events assessed by the 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 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 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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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. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is an MSKCC investigator-initiated,  single-center, randomized, open-label, phase 
2 study to evaluate the activity of durvalumab alone (Arm 1) or durvalumab in combination 
with tremelimumab (Arm 2) in patients with recurrent or persistent endometrial carcinoma or 
endometrial carcinosarcoma.  The safety and tolerability of these agents in this patient 
population will also be evaluated. 
 
Patients will be randomized to Arm 1: durvalumab alone or Arm 2: durvalumab with 
tremelimumab. Randomization will be accomplished by the method of random permuted 
block, and patients will be stratified by histology (stratum 1: endometrial carcinosarcoma 
patients OR MSI-high endometrial carcinoma patients and stratum 2: other histologies). We 
will limit enrollment of stratum 1 to 10 patients per arm. 
 
MSI-high patients will be identified based on immunohistochemistry or MSI testing of tumor 
by department of pathology or via known mutations found in mismatch repair genes via the 
Integrated Mutation  Profiling of Actionable Cancer Targets (IMPACT) assay through MSKCC 
IRB# 12-245. 
 
Each cycle will be 28 days in duration. Patients will receive study treatment until disease 
progression, intolerable toxicity, elective withdrawal from the study, study completion, or 
study termination. 
 
Radiologic tumor assessment will be repeated every 8 weeks +/- 7 days for the first 48 
weeks and then every 12 weeks +/- 7 days until PD. For patients who remain progression 
free 2 years post completion of protocol directed treatment, every 6 months +/- 1 month. 
Safety will be evaluated through the monitoring of all serious and non-serious AEs and 
irAE’s, graded according to the current version of National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE v. 4.03). 
 
 
4.3 
Intervention 
 
Eligible patients will undergo screening and baseline procedures per the Study Schedule. 
Study inclusion and exclusion criteria will be applied per section 6.0. Enrolled patients will 
receive treatment on one of two treatment arms based on randomization: 
Arm 1: Patients will receive intravenous (IV) infusion of durvalumab 1500mg Fixed Dose 
every 4 weeks until patient develops a loss of clinical benefit or experiences unacceptable 
toxicities. 


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Arm 2:  Patients will receive durvalumab + tremelimumab combination therapy. Patients will 
receive 1500 mg Fixed Dose durvalumab via IV infusion q4w for up to 4 cycles and 75 mg 
tremelimumab via IV infusion q4w for up to 4 cycles, and then continue 1500 mg Fixed Dose 
durvalumab every 4 weeks until patient develops a loss of clinical benefit or experiences 
unacceptable toxicities. 
Dosing outside the window should be discussedwiththe Principal Investigator. 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 (±5 
minutes). A 1 hour observation period is required after the first infusion of single agent 
durvalumab and combination durvalumab and tremelimumab. If no clinically significant infusion 
reactions are observed during or after the first cycle, subsequent infusion observation periods 
can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab and 
tremelimumab infusion). 
Treatment will continue until progression, intolerance, withdrawal, study completion, or study 
termination. 
Radiologic tumor assessment will be repeated every 8 weeks +/- 7 days for the first 48 
weeks and then every 12 weeks +/- 7 days until PD. For patients who remain progression 
free 2 years post completion of protocol directed treatment, every 6 months +/- 1 month. 
Patients who discontinue treatment for reasons other than progression may continue efficacy 
assessments until progression is demonstrated. Patients who demonstrate radiologic 
progression by RECIST criteria may be considered for continued therapy (but not primary 
efficacy analysis) if they are deemed to be clinically benefiting, according to predetermined 
permitted criteria (section 12.4). Safety will be evaluated in this study through the monitoring 
of all serious and non-serious AEs and irAEs, graded according to the current version of the 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTC v.4.03). 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
The   Investigational Products   Supply   section   of   AstraZeneca/MedImmune 
will   supply 
durvalumab and tremelimumab to the investigator as a solution for infusion after dilution. 
5.1 
Tremelimumab 
Background: 
Tremelimumab (formerly CP-675,206) is a human immunoglobulin  (Ig)G2 monoclonal 
antibody (mAb) being investigated  as a cancer immunotherapeutic agent. Tremelimumab 
is specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; cluster of 
differentiation  [CD]152), a cell surface receptor that is expressed primarily on activated T 
cells and acts to inhibit their activation. 
 
Formulation: 
Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 
20 mM histidine/histidine  hydrochloride,  222 mM trehalose dihydrate,  0.02% 
(weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), 
pH 5.5. 
 
Date: 


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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. Tremelimumab must be used within 
the individually assigned expiry date on the label. The normal fill volume is 20 mL. 
Storage: 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be 
frozen.  Tremelimumab is administered as an IV infusion after dilution in sterile, 
normal saline for injection. The product should be protected from light when not in 
use. 
Refer to the Tremelimumab investigator brochure for detailed information about this agent. 
 
5.2 
Durvalumab (MEDI4736) 
 
The Investigational  Products Supply section of AstraZeneca/MedImmune  will supply 
durvalumab to the investigator as a concentrate for solution for infusion. 
Formulation/packaging/storage 
 
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. Durvalumab must be 
used within the individually assigned expiry date on the label. 
The investigational product is supplied as a vialed liquid solution in clear 10R glass vials 
closed with an elastomeric stopper and a flip-off cap overseal. Each vial contains 500 mg 
(nominal) of active investigational product at a concentration of 50 mg/mL (500 mg/vial). The 
solution will be diluted with 0.9% (weight/volume) saline for IV infusion. 
Unopened vials of liquid Durvalumab must be stored at 2°C to 8°C (36°F to 46°F). 
Durvalumab must be used within the individually assigned expiry date on the label. 
In use storage and stability 
 
Total in-use storage time from needle puncture of Durvalumab vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2-8°C (36-46°F). If in-use 
storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. Durvalumab  does not contain preservatives and any unused portion must be 
discarded. 
 
 
 
 
Study drug preparation 


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Calculate the dose volume of Durvalumab and number of vials needed for the subject to 
achieve the accurate dose according to Appendix B. 
Preparation of infusion bags 
 
The preparation of infusion bags should be done under aseptic conditions by trained 
personnel; it should not be prepared on the ward. 
 
An additional volume of 0.9% (weight/volume) saline equal to the calculated volume of 
durvalumab to be added to the IV bag must be removed from the bag prior to addition of 
durvalumab. 
The calculated volume of durvalumab is then added to the IV bag, and the bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag. 
Prior to the start of the infusion, ensure that the bag contents are at room temperature to 
avoid an infusion reaction due to the administration of the solution at low temperatures. 
Vials should be used for specific subjects and should not be shared between subjects. 
 
Patient weight at baseline should be used for dosing calculations in patients ≤30 kg unless 
there is a ≥10% change in weight. Dosing day weight can be used for dosing calculations 
instead of baseline weight per institutional standard. 
Dose administration 
 
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-μm in-line filter. 
Less than 55 minutes is considered a deviation. 
The IV line will be flushed with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. 
The Durvalumab  solution should not be infused through an IV line in which other solutions or 
medications are being administered. 
Monitoring of dose administration 
 
Subjects will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessments (Section 10.0). 
In the event of a Grade ≤ 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50%, or interrupted until resolution of the event (up to 4 hours) and re-initiated 
at 50% of the initial rate until completion of the infusion. For subjects with a Grade ≤ 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial 
rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 


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medications per institutional standard may be administered at the discretion of the 
investigator.  If the infusion-related reaction is Grade ≥ 3 or higher in severity, study drug will 
be discontinued. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The 
study site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit subjects to an intensive care unit if necessary. 
Durvalumab + tremelimumab combination therapy 
 
Patients in the durvalumab + tremelimumab combination therapy group will receive 1500 mg 
durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV 
infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on 
Week 16. Dosing outside the window should be discussed with the Principal Investigator. 
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 (±5 minutes). 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 at the 
Investigator’s discretion (suggested 30 minutes after each durvalumab and tremelimumab 
infusion). 
Study drug preparation of durvalumab and tremelimumab 
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. 
 
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed: 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
 
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, 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. 


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For patients <30kg, Calculate the dose volume of durvalumab and tremelimum ab 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 from needle puncture to 
start of administration 
4 hours at room temperature, 24 hours at 2°C to 8°C 
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 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 or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
tremelimumab  vial to the start of administration should not exceed: 
 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
 
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, with a final tremelimumab concentration ranging from 


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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. 
For patients <30 kg, Calculate the dose volume for tremelimumab and number of vials needed 
for subject to achieve the accurate dose. 
 
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 from needle puncture 
to start of administration 
4 hours at room temperature, 24 hours at 2°C to 
8°C 
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 table, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded. 
 
Monitoring of dose administration 
Patients will be monitored during and after the infusion with assessment of vital signs 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 


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rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator.  If the infusion-related reaction is ≥Grade 3 or higher in severity, study drug will 
be discontinued. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The 
study site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit patients to an intensive care unit if necessary. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
1. 
Subjects must have recurrent or persistent endometrial carcinoma (including: 
Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated  carcinoma, 
dedifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial  carcinoma, 
adenocarcinoma not otherwise specified (N.O.S.), mucinous adenocarcinoma, 
squamous cell carcinoma, and transitional cell carcinoma) or endometrial 
carcinosarcoma).  Histologic documentation of diagnosis of carcinoma is required. 
MSI-high patients will be identified based on immunohistochemistry or MSI testing of 
archival tumor specimens by department of pathology or via known mutations found 
in mismatch repair genes via the  Integrated Mutation Profiling of Actionable Cancer 
Targets (IMPACT) assay through MSKCC IRB# 12-245. 
 
2. 
All patients must have measurable disease. Measurable disease is defined by 
RECIST (version 1.1). Measurable disease is defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be recorded). 
Each lesion must be ≥ 10 mm when measured by CT, MRI or caliper measurement 
by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph nodes must be ≥ 
15 mm in short axis when measured by CT or MRI. 
 
3. 
Patients must have at least one “target lesion” to be used to assess response on this 
protocol as defined by RECIST version 1.1 (Section 12.0). Tumors within a previously 
irradiated field will be designated as “non-target” lesions unless progression is 
documented or a biopsy is obtained to confirm persistence at least 90 days following 
completion of radiation therapy. 
 
4. 
Age ≥ 18 years and life expectancy of ≥ 12 weeks. 
 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 
6. 
Resolution of (non-laboratory) adverse effects of recent surgery, radiotherapy, or 
chemotherapy to Grade ≤1 prior to first study treatment (with the exception of 
alopecia or neuropathy). 
 
7. 
Patients must have had one prior platinum-based chemotherapeutic regimen for 
management of endometrial carcinoma or carcinosarcoma. Initial treatment may 
include chemotherapy, chemotherapy and radiation therapy, and/or 


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consolidation/maintenance therapy. Chemotherapy administered in conjunction with 
primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy 
regimen. 
 
8. 
Patients are allowed to receive, but are not required to receive, three additional 
cytotoxic regimen for management of recurrent or persistent disease.   Hormonal 
therapies will not count toward the prior regimen limit. 
 
9. 
Adequate normal organ and marrow function defined by the following laboratory 
results obtained within 14 days prior to first treatment: 
 
 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
 
Platelet ≥ 100 x 109/L (>100,000 per mm3) 
 
Hemoglobin ≥ 9.0 g/dL 
 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  (Unless 
Gilbert’s Syndrome, for which Bilirubin ≤ 3 x institutional upper limit of normal 
(ULN) , without concurrent clinically significant liver disease) 
 
AST (SGOT)/ALT (SGPT) ≤ 3 x institutional upper limit of normal (ULN) unless 
liver metastases are present, in which case it must be ≤ 5x ULN 
 
Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) 
 
10. 
Female subjects must either be of non-reproductive potential (i.e., post-menopausal 
by history: ≥55 years old and no menses for ≥1 year without an alternative medical 
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of 
bilateral oophorectomy) or must have a negative serum pregnancy test upon study 
entry. 
 
11. 
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. 
 
12. 
Patients must have been enrolled, or agree to consent to the companion genomic 
profiling study MSKCC IRB# 12-245. Results must be available before starting 
treatment on protocol. 
 
13. 
Patients must have signed an approved informed consent and authorization 
permitting release of personal information. 
 
 
6.3 
Subject Exclusion Criteria 
 
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 receipt of an investigational product during 
the last 4 weeks. 
3. 
Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or any 
anti-CTLA4, including tremelimumab. 
4. 
History of another primary malignancy except for: 


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• 
Malignancy treated with curative intent and with no known active disease ≥3 
years before the first dose of study drug and of low potential risk for 
recurrence 
 
• 
Adequately  treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
 
• 
Adequately treated carcinoma in situ without evidence of disease (eg, cervical 
cancer in situ) 
 
• 
Adequately treated stage 1 breast cancer. 
 
5. 
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) < 21 
days prior to the first dose of study drug.  Receipt of the last dose of hormonal 
therapy within < 7 days prior to the first dose of study drug. 
6. 
Any prior radiation therapy must be discontinued at least four weeks prior to 
registration. 
7. 
At least 4 weeks must have elapsed since the patient underwent any major surgery 
(e.g., major: laparotomy, laparoscopy) There is no delay in treatment for minor 
procedures (e.g., central venous access catheter placement). 
8. 
Patients should not be candidates for further surgical resection or definitive tumor- 
directed XRT based upon prior therapies and/or extent of disease at recurrence. 
9. 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) 
10. 
Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab or durvalumab and 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.  Patients who have received acute, low dose, systemic 
immunosuppressant medications (e.g., dexamethasone for nausea or steroids as CT 
scan contrast premedication) may be enrolled. 
11. 
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE > Grade 1 
12. 
Active or prior documented autoimmune disease within the past 2 years 
NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 
13. 
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis) 
14. 
History of primary immunodeficiency 


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15. 
History and/or confirmed pneumonitis or interstitial lung disease 
 
16. 
History of allogeneic organ transplant 
 
17. 
History of hypersensitivity to durvalumab or any excipient 
 
18. 
History of hypersensitivity to tremelimumab 
 
19. 
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 
 
20. 
Known history of previous clinical diagnosis of tuberculosis 
 
21. 
History of leptomeningeal carcinomatosis 
 
22. 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab or tremelimumab. 
23. 
Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results 
24. 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, 
inclusive of but not limited to surgery, radiation and/or corticosteroids. 
25. 
Subjects with uncontrolled seizures. 
 
26. 
Patients who are pregnant or breastfeeding or patients of reproductive potential who 
are not willing to employ effective birth control 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 
27. 
History of small or large bowel obstruction within 3 months of registration, including 
subjects with palliative gastric drainage catheters. Subjects with palliative diverting 
ileostomy or colostomy are allowed if they have been symptom free for more than 3 
months. 
28. 
Ongoing bowel perforation or presence of bowel fistula or abscess within 3 months of 
registration. 
29. 
Subjects with refractory ascites, defined as ascites needing drainage catheter or 
therapeutic paracentesis more often than every 4 weeks. 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator or research team within the Gynecologic Medical Oncology Group at 


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Memorial Sloan Kettering Cancer Center (MSKCC). Patient recruitment will occur in the 
Gynecologic Medical Oncology clinics at MSKCC. The investigator will discuss the study with 
suitable participants, and should the patient consent to proceed with protocol therapy, will 
enroll their patients in the research study. Approximately 4 patients will accrue onto this study 
per month. All participants will be women. 
8.1 
PRETREATMENT EVALUATION 
 
Within 28 days prior to treatment start: 
• Written informed consent 
• 
History and Physical examination 
• Review of concomitant medications 
• Vital signs (blood pressure, heart rate and temperature), weight and height 
• 
ECOG Performance status 
• Toxicity assessment 
• 12-lead ECG (in triplicate) 
• Radiographic tumor measurements (CT C/A/P, MRI) 
• Confirm sufficient tissue is available  (10-20 PPFE slides or tissue block). 
 
Within 14 days prior to treatment start: 
• Complete Blood Count (CBC) with differential and platelets 
• Comprehensive profile (BUN, creatinine, sodium, potassium, chloride, CO2, calcium, 
glucose, total bilirubin, total protein, albumin, alkaline phosphatase, AST, ALT) 
• 
Thyroid function tests (TSH and fT4) 
• 
Amylase 
• 
Lipase 
• 
Coagulation tests: prothrombin time, APTT and INR (PT/PTT) 
• Magnesium 
• Uric Acid 
• CA125 
• Urinalysis 
• Pregnancy test (in women of child bearing potential) 
 
ECGs are required during screening and on Cycle 1 Day 1. See section 10. 
Vital signs will be evaluated according to the assessment schedules. See section 10. 
Situations in which vital signs results should be reported as AEs are described in Section 11.0. 
9.1 
TREATMENT/INTERVENTION PLAN 
 
All subjects will be randomized to one of two treatment arms in a 1:1 fashion. 
 
Arm 1: Patients will receive intravenous (IV) infusion of durvalumab 1500mg Fixed Dose 
every 4 weeks until patient develops a loss of clinical benefit or experiences unacceptable 
toxicities. 
Arm 2:  Patients will receive durvalumab + tremelimumab combination therapy. Patients will 
receive 1500 mg Fixed Dose durvalumab via IV infusion q4w for up to 4 cycles and 75 mg 
tremelimumab via IV infusion q4w for up to 4 cycles, and then continue 1500 mg Fixed Dose 
durvalumab every 4 weeks until patient develops a loss of clinical benefit or experiences 
unacceptable toxicities. 


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Dosing outside the window should be discussed with the Principal Investigator. 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 single agent durvalumab and 
combination durvalumab and tremelimumab. If no clinically significant infusion reactions are 
observed during or after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion (suggested 30 minutes after each durvalumab single agent infusion 30 
minutes  after the combination durvalumab and tremelimumab infusion). 
1. 
Patients will receive study treatment until disease progression, intolerable toxicity, 
elective withdrawal from the study, study completion, or study termination. 
 
2. Radiologic tumor assessment will be repeated every 8 weeks +/- 7 days for the first 48 
weeks and then every 12 weeks +/- 7 days until PD. For patients who remain progression free 
2 years post completion of protocol directed treatment, every 6 months +/- 1 month. 
 
3. 
Safety will be evaluated in this study through the monitoring of all serious and non- 
serious AEs and irAEs, graded according to the current version of the National Cancer Institute 
Common Terminology Criteria for Adverse Events. Procedures to be conducted during the 
treatment phase of the study are presented in the Schedule of Assessments (Section 10.0). 
 
4. 
Pre- and post-treatment blood and serum samples, as well as archival tumor tissue 
(when available) will be collected for biomarker analysis (as per Appendix E). 
 
5. 
Assessments for subjects who have completed durvalumab and tremelimumab 
treatment and achieved disease control, or have discontinued durvalumab or tremelimumab 
due to toxicity in the absence of progressive disease are provided in Appendix A. 
 
Assessments for subjects who have discontinued durvalumab or tremelimumab treatment due 
to PD are presented in Appendix A. 
Duration of treatment and criteria for retreatment with durvalumab and tremelimumab 
combination 
On both study arms, the patients will continue to receive the study drugs as long as they 
continue to experience clinical benefit and have no unacceptable toxicities. For patients in the 
durvalumab + tremelimumab arm, patients who complete the 4 dosing cycles of the 
combination of durvalumab and tremelimumab portion of the regimen (with clinical benefit per 
Investigator judgment), but subsequently have evidence of PD during the durvalumab 
monotherapy portion of the combination regimen, according to RECIST 1.1, may receive re- 
treatment with another 4 cycles of the combination regimen (only once). 
Before restarting their assigned re-treatment, the Investigator should ensure that the patient: 
 
a. Does not  have  any significant,  unacceptable, or irreversible  toxicities  that indicate 
continuing treatment will not further benefit the patient 
 
b. Still  fulfils  the  eligibility  criteria  for  this  study,  including  re-consenting  to  restart 
durvalumab and tremelimumab 


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c. Has not have received an intervening systemic anticancer therapy after their assigned 
treatment discontinuation. 
 
d. Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur with the same frequency as during the initial 
treatment. 
 
During the retreatment period, patients receiving durvalumab + tremelimumab may resume 
durvalumab dosing at 1500 mg q4w with 75 mg of tremelimumab q4w for 4 cycles each. 
Patients will then continue with durvalumab monotherapy at 1500 mg q4w, beginning at Week 
16, 4 weeks after the last dose of combination regimen therapy. 
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. 
Patients who AstraZeneca and/or the Investigator determine may not continue treatment will 
enter follow-up. 
If a patient withdraws from participation in the study, then his or her enrollment/randomization 
code cannot be reused.  Withdrawn patients will not be replaced. 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
All assessments to be performed pre-infusion unless stated otherwise. A Cycle is 28 Days. 
 
Treatment Arm 1: Durvalumab 
Parameter 
Screening 
Cycle 1 
Cycles 2-4 
Cycles 5 onward 
End of 
Treatment 
Follow- 
up 
Day 
Within 28 
days 
beforea 
Within 
14 
days 
before 
Da 
y 1 
Da 
y 8 
Day 
15 
Day 
1 
Day 
15 
Day 1 
Day 15 
90 days 
post- 
dose 
Consent 
x 
Medical History 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Request Archival 
tumor tissue 
x 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
Vital Signs (BP, HR, 
and temperature) 
height e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Event 
Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC 
x 
x 
x 
x 
x 
Comprehensive 
Profile 
x 
x 
x 
x 
x 
x 
x 
x 


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Parameter 
Screening 
Cycle 1 
Cycles 2-4 
Cycles 5 onward 
End of 
Treatment 
Follow- 
up 
Day 
Within 28 
days 
beforea 
Within 
14 
days 
before 
Da 
y 1 
Da 
y 8 
Day 
15 
Day 
1 
Day 
15 
Day 1 
Day 15 
90 days 
post- 
dose 
TSH 
x 
x 
x 
x 
x 
Free T4f 
x 
x 
x 
x 
x 
PT/PTT 
x 
As clinicallyindicated 
Magnesium 
x 
Amylase 
x 
x 
x 
x 
x 
Lipase 
x 
x 
x 
x 
x 
Uric Acid 
x 
x 
x 
x 
x 
CA-125 
x 
x 
x 
X 
Hepatitis B surface 
antigen 
x 
Hepatitis B Core Ab 
(total) 
x 
Hepatitis C antibody 
x 
HIV antibodyg 
x 
Urinalysis 
x 
x 
x 
Pregnancy Test d 
x 
As clinicallyindicated 
Research bloods b 
Days 1,8,29, and 57 
12- Lead ECG (in 
triplicate) c 
x 
x 
As clinicallyindicated 
Durvalumab 
x 
x 
x 
Radiographic disease 
assessmenth 
x 
Every 8 weeks +/- 7 days x 48 weeks, then every 12 
weeks +/- 7 days 
(For patients who remain progression free 2 years post 
completion of protocol directed treatment, every 6 
months +/- 1 month.) 
x 
 
 
Treatment Arm 2: Durvalumab and Tremelimumab 
Parameter 
Screening 
Cycle 1 
Cycles 2-4 
Cycles 5 onward 
End of 
Treatment 
Follow- 
up 
Day 
Within 28 
days a 
Within 
14 
days 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
15 
Day 1 
Day 15 
90 days 
post- 
dose 
Consent 
x 
Medical History 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Request Archival 
tumor tissue 
x 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 


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NOTE:  3 day window for all parameter’s (except for ECG [see c] and Radiographic disease 
assessment [+/- 7days]) 
a If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to 
be repeated at Cycle 1 Day 1. Results for cbc and liver enzymes (AST/ALT) must be available and 
reviewed before commencing an infusion. 
b Research bloods will consist of 6 CPT tubes and will be drawn at 4 time points: 
• 
Day 1 (Cycle 1, Day 1) 
• 
Day 8 (Cycle 1, Day 8) 
• 
Day 29 (Cycle 2, Day 1) – may be drawn up to 3 days prior to day 29 
Screening 
Parameter 
Cycle 1 
Cycles 2-4 
Cycles 5 onward 
End of 
Follow- 
Treatment 
up 
Day 
Within 28 
days a 
Within 
14 
days 
Day 
Day 
Day 
Day 
1 
8 
15 
1 
Day 
15 
Day 1 
Day 15 
90 days
post- 
dose 
Vital Signs (BP, HR, 
and temperature) 
height e 
Adverse Event 
Assessment 
CBC 
Comprehensive 
Profile 
TSH 
Free T4 f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT/PTT j 
Magnesium 
Amylase 
Lipase 
Uric Acid 
CA-125 
Hepatitis B surface 
antigen 
Hepatitis B Core Ab 
(total) 
Hepatitis C antibody 
HIV antibody g 
As clinicallyindicated 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
Pregnancy Test d 
Research bloods b 
12- Lead ECG (in 
triplicate) c 
Durvalumab 
Tremelimumab 
x 
x 
x 
x 
As clinicallyindicated 
Days 1,8,29, and 57 
x 
x 
x 
x 
As clinicallyindicated 
x 
x 
x 
Radiographic disease 
assessmenth 
x 
Every 8 weeks +/- 7 days x 48 weeks, then every 12 
weeks +/- 7 days 
(For patients who remain progression free 2 years post 
completion of protocol directed treatment, every 6 
months +/- 1 month.) 
x


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• 
Day 57 (Cycle 3, Day 1) – may be drawn up to 3 days prior to day 57 
c ECGs will be obtained in triplicate (with 2-5 minute lag time between each).  All 12-lead ECGs 
should be recorded while the subject is in the supine position. Twelve-lead ECGs will be obtained 
after the subject has been resting in a supine position for at least 5 minutes in each case. On Cycle 
1, Day 1:  ECGs should be taken within an hour prior to the start of the infusion and at least one time 
point 0 to 3 hours after the infusion. 
d      Pre-menopausal female subjects of childbearing potential only 
e  Subjects will have their blood pressure and pulse measured before, during, and after each infusion 
at the following times (based on a 60-minute infusion): 
• 
At the beginning of the infusion (at -30 to 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
• 
For the first infusion only, in the 1 hour observation period post-infusion: 30 and 60 minutes 
after the infusion (i.e., 90 and 120 minutes from the start of the infusion) (±5 minutes) 
• 
If no clinically significant infusion reactions are observed during or after the first cycle, 
subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 
minutes after each durvalumab and tremelimumab infusion). 
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements 
should follow the principles as described above or more frequently if clinically indicated. 
f    Free T4 will only be measured if TSH is abnormal. Free T4 should also be measured if there is 
clinical suspicion of an adverse event related to the endocrine system. 
g If already done at MSK prior to study entry, does not need to be repeated. 
h  irRECIST assessments will only be completed for patients continuing treatment beyond PD. 
 
Post-treatment follow up. 
 
All patients will need a study completion/early termination visit 28 +/- 3 days after they receive the 
last infusion of the study treatment. If the 28 day follow up visit coincides with the progression of 
disease (POD) visit, then assessments for both visits can be combined. The patients will continue to 
be followed for toxicity for 90 days after the last infusion of the drug. 
11.1 TOXICITIES/SIDE EFFECTS 
 
The dose delay and reduction instructions provided in this section are intended to serve as 
guidelines to allow ongoing treatment for patients experiencing clinical benefit without signs 
or symptoms of progression while ensuring patient safety. Patients may temporarily suspend 
dosing of study drug for up to 14 days if they experience toxicity that is considered related to 
study drug and requires that a dose be held. Patients who miss ≥ 28 consecutive days of 
scheduled study treatment because of drug-related AEs will be discontinued from the study. 
Exceptions may be made after discussion with and approval by the Principal Investigator. 
Patients may suspend dosing of study drug for radiation therapy or surgery that is considered 
by the treating physicians to be of clinical benefit for the patient. After completion of the 
intervention, patients may restart the study drug as long as all criteria for dosing are met and 
there is no evidence of disease progression (unless approved by PI and sponsor as noted 
previously). 
For adverse events (AEs) that are considered at least partly due to administration of 
durvalumab or tremelimumab the following dose adjustment guidance may be applied: 


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• 
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. 
• 
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 (see Table 4). 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 colitis, pneumonitis, 
hepatitis/hepatotoxicity,  neuropathy/neuromuscular toxicity, endocrinopathy,  dermatitis, 
pancreatitis and nephritis . 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 colitis, 
pneumonitis, hepatitis/hepatotoxicity,  neuropathy/neuromuscular toxicity, endocrinopathy, 
dermatitis, pancreatitis and nephritis  should be considered to be immune-related. 
Dose modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
Tables 5 and 6. 
 
In addition, management guidelines for adverse events of special interest (AESIs ) are detailed in 
Section 11.4.3. All toxicities will be graded according to NCI CTCAE v4.03. 
 
For patients who are being treated with both durvaluab and tremelimumab, both agents will be 
held/discontinued in the event of a toxicity as described in Tables 4-6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE 4: 


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Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non Immune- 
mediated Reactions (MEDI4736 Monotherapy or Combination therapy with Tremelimumabor Tremelimumab 
Monotherapy) 28 October 2021 Version 
Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen 
will be made to manage potential immune-related AEs based on 
severity of treatment-emergent toxicities graded per NCI CTCAE 
v4.03 (unless indicated otherwise). 
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 
of the start of the immune0mediated adverse event 
(imAE) 
• 
Grade 3 recurrence of a previously experienced 
treatment-related imAE 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 asymptomatic amylase or lipase levels of > 2.0xULN, 
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. 


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Specific Immune-mediated Reactions 
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. 
− 
Suspected pneumonitis should be 
confirmed with radiographic imaging 
and other infectious and disease- 
related aetiologies excluded, and 
managed 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. 
− 
Consider Pulmonary and Infectious 
Disease Consults. 
Grade 1 
(asymptomatic, 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications 
required. However, consider 
holding study drug/study 
regimen dose as clinically 
appropriate and during 
diagnostic work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms, pulse 
oximetry (resting and exertion), and 
laboratory work-up and then as 
clinically indicated. 
− 
Consider Pulmonary and Infectious 
Disease consults. 
Grade 2 
(symptomatic; 
medical 
intervention 
indicated; limiting 
instrumental 
ADL) 
Hold study drug/study regimen 
dose until Grade 2 resolution 
to Grade ≤1. 
• 
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 (<10mg prednisone 
or equivalent). 
For Grade 2 (mild to moderate new 
symptoms): 
− 
Monitor symptoms daily and consider 
hospitalization. 
− 
Obtain Pulmonary and Infectious 
Diseases Consults; consider 
discussing with Clinical Study Lead, 
as needed. 
− 
Promptly start systemic steroids (eg, 
prednisone 1 to 2 mg/kg/day PO or 
IV equivalent). 
− 
Reimage as clinically indicated, 
Consider Pulmonary and Infectious 
Disease Consults. 
− 
If no improvement within 2 to 3 days, 
additional workup should be 
considered and prompt treatment with 
IV methylprednisolone 2 to 
4 mg/kg/day started 


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− 
If still no improvement within 2 to 3 
days despite IV methylprednisone at 
2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
tumor necrosis factor (TNF) 
inhibitors (eg, infliximab at 5 mg/kg 
IV once, may be repeated at 2 and 6 
weeks after initial dose at the 
discretion of the treating provider or 
relevant practice guidelines). 
Caution: It is important to rule out 
sepsis and refer to infliximab label 
for general guidance before using 
infliximab.  Consider, as necessary, 
discussing with Clinical Study Lead. 
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 consults; consider discussing 
with Clinical Study Lead, as needed. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, oxygen). 
− 
If no improvement within 2 days, 
additional workup should be 
considered and prompt treatment with 
additional immunosuppressive 
therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg IV, maybe 
repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating 
provider or relevant practice 
guidelines). Caution: rule out sepsis 
and refer to infliximab label for 
general guidance before using 
infliximab. 
Diarrhea/Colitis 
Large intestine 
perforation/Intestine 
perforation 
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). 
− 
When symptoms or evaluation 
indicate a perforation is suspected, 
consult a surgeon experienced in 
abdominal surgery immediately 
without any delay. 
− 
Permanently discontinue study drug 
for any grade of intestinal 
perforation 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (eg, disease progression, 
other medications, or infections), 


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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, including 
perforation. 
− 
Use analgesics carefully; they can 
mask symptoms of perforation and 
peritonitis. 
Grade 1 
(stool frequency 
of 
<4 over baseline 
per day) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening 
symptoms. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (eg, 
American Dietetic Association colitis 
diet), and loperamide and other 
supportive care measures. 
− 
If symptoms persist consider 
checking lactoferrin; if positive treat 
as Grade 2 below.  If negative and no 
infection, continue Grade 1 
management 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 
6 over baseline 
per day) 
(Colitis: 
abdominal pain; 
mucus or blood in 
stool) 
(Perforation: 
symptomatic; 
medical 
intervention 
indicated*) 
*”medical 
intervention” is 
not invasive 
Hold study drug/study regimen 
until resolution to Grade ≤1 
• 
If toxicity improves to 
Grade ≤1, then study 
drug/study regimen  can be 
resumed after completion 
of steroid taper (<10mg 
prednisone, or 
equivalent). 
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 2 to 
3 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, gastrointestinal (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 2 to 3 
days despite 1 to 2 mg/kg IV 
methylprednisolone, promptly start 
immunosuppressives such as 
infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating 
provider or relevant practice 
guidelines. Caution: it is important 
to rule out bowel perforation and 
refer to infliximab label for general 
guidance before using infliximab. 
− 
If perforation is suspected, consult a 
surgeon experienced in abdominal 


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surgery immediately without any 
delay. 
− 
Consider, as necessary, discussing 
with Clinical Study Lead if no 
resolution to Grade ≤1 in 3 to 4 days. 
Grade 3 or 4 
(Grade 3 
Diarrhea: stool 
frequency of ≥7 
over baseline per 
day; 
Grade 4 Diarrhea: 
life threatening 
consequences) 
(Grade 3 Colitis: 
severe abdominal 
pain, change in 
bowel habits, 
medi-cal 
intervention 
indicated, 
peritoneal signs; 
Grade 4 Colitis: 
life-threatening 
consequences, 
urgent 
intervention 
indicated) 
(Grade 3 
Perforation: 
severe symptoms, 
elective* 
operative 
intervention 
indicated; 
Grade 4 
Perforation: life- 
threatening 
consequences, 
urgent 
intervention 
indicated) 
*This guidance 
anticipates that 
Grade 3 operative 
interventions  of 
perforations are 
usually not 
elective 
Grade 3 
− 
For patients treatet 
with durvalumab 
monotherapy, hold 
study drug/study 
regimen until 
resolution to Grade 
≤1; study drug/study 
regimen can be 
resumed after 
completion of steroid 
taper (<10 mg 
prednisone per day, 
or equivalent). 
− 
For patients treated 
with durvalumab in 
combination with 
other products (not 
tremelimumab), 
decision to be made 
at the discretion of 
the study 
investigator, in 
discussion with 
AstraZeneca Clinical 
Study Lead. 
− For p at ient s t reat ed 
wit h durvalumab in 
combinat ion wit h 
t remelimumab or 
t remelimumab 
monot herap y , 
Permanently 
discontinue study 
drug for 1) Grade 3 
diarrhea colitis or 2) 
Any grade large 
intestine perforation 
in any patient treated 
with immune 
checkpoint inhibitor 
(ICI). 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 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 2 days 
continue steroids and promptly add 
further immunosuppressant agents 
(e.g., infliximab at 5 mg/kg IV, may 
be repeated at 2 and 6 weeks after 
initial dose at the discretion of the 
treating provider or relevant practice 
guidelines). 
Caution: Ensure GI consult to rule 
out bowel perforation and refer to 
infliximab label for general guidance 
before using infliximab.  If 
perforation is suspected, consult a 
surgeon experienced in abdominal 
surgery immediately without any 
delay. 


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Grade 4 
− 
Permanently 
discontinue study 
drug/study regimen. 
Hepatitis 
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Elevations 
in AST, ALT or 
TB as Described 
Below 
General Guidance 
For Any Grade: 
− 
Patients should be thoroughly 
evaluate to rule out alternative 
etiology (e.g, viral hepatitis, disease 
progression, concomitant 
medications, worsening of liver 
cirrhosis [e.g., portal vein 
thrombosis]). 
− 
Monitor and evaluate liver function 
test: AST, ALT, ALP, and TB. 
− 
For hepatitis B + patients: evaluate 
quantitative HBV viral load, 
quantitative Hepatitis B surface 
antigen (HBsAg), or Hepatitis B 
envelope antigen (HBeAg). 
− 
For hepatitis C (HCV) + patients: 
evaluate quantitative HCV viral load. 
− 
Consider consulting Hepatology or 
Infectious Diseases specialists 
regarding changing or starting 
antiviral HBV medications if HBV 
viral load is >2000 IU/ml. 
− 
Consider consulting Hepatology or 
Infectious Diseases specialists 
regarding changing or starting 
antiviral HCV medications if HCV 
viral load has increased by ≥2-fold. 
− 
For HCV+ with Hepatitis B core 
antibody (HBcAb) +: Evaluate for 
both HBV and HCV as above. 
− 
Isolated AST or 
ALT >ULN and 
≤5.0×ULN, 
whether normal 
or elevatedat 
baseline 
• 
No dose modifications. 
• 
If ALT/AST elevations 
represents significant 
worsening based on 
investigator assessment, 
then treat as described for 
elevations in the row 
below. 
• 
For all transaminase 
elevations, see instructions 
at bottom of shaded area if 
transaminase rise is not 
isolated but (at any time) 
occurs in setting of either 
increasing bilirubin or 
signs of DILI/liver 
decompensation. 
− 
Isolated AST or 
ALT >5.0×ULN 
and ≤8.0×ULN, if 
normal at 
baseline 
Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤5.0xULN. 
• 
If toxicity worsens, then 
treat as described for 
− 
Regular and frequent checking of 
LFTs (e.g., every 1 to 3 days) until 
elevations of these are improving or 
resolved. 


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Isolated AST or 
ALT 
>2.0×baseline 
and ≤12.5×ULN, 
if elevated>ULN 
at baseline 
elevation in the row 
below. If toxicity 
improves to AST or ALT 
≤5.0xULN, resume study 
drug/study regimen after 
completion of steroid 
taper (<10mg prednisone 
or equivalent). 
• 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria, in the absence 
of any alternative cause.b 
Recommend consult hepatologist; 
consider abdominal ultrasound, 
including Doppler assessment of liver 
perfusion. 
− 
Consider, as necessary, discussing 
with Clinical Study Lead. 
− 
If event is persistent (>2 to 3 days) or 
worsens, and investigator suspects 
toxicity to be an imAE, start 
prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
− 
If still no improvement within 2 to 3 
days despite 1 to 2 mg/kg/day  of 
prednisone PO or IV equivalent, 
consider additional workup. If still no 
improvement within 2 to 3 days 
despite 2mg/kg/day of IV 
methylprednisolone, consider 
additional abdominal workup 
(including liver biopsy) and imaging 
(i.e., liver ultrasound), and consider 
starting additional 
immunosuppressants. (e.g., 
mycophenolate mofetil 0.5 – 1 g 
every 12 hours then taper in 
consultation with hepatology consult 
or relevant practice guidelines). 
Discuss Clinical Study Lead if 
mycophenolate mofetil is not 
available. Infliximabshould NOT 
be used. 
Isolated AST or 
ALT >8.0×ULN 
and ≤20.0×ULN, 
if normal at 
baseline 
Isolated AST or 
ALT >12.5×ULN 
and ≤20.0×ULN, 
if elevated>ULN 
at baseline 
• Hold study drug/study 
regimen dose until 
resolution to AST or ALT 
≤5.0×ULN. Resume study 
drug/study regimen if 
elevations downgrade to 
AST or ALT ≤5.0×ULN 
and after completion of 
steroid taper (<10mg 
prednisone, or equivalent). 
• Permanently discontinue 
study drug/study regimen 
if the elevations do not 
downgrade to AST or 
ALT ≤5.0×ULN within 
14 days 
− 
Regular and frequent checking of 
LFTs (e.g., every 1-2 days) until 
elevations of these are improving or 
resolved. 
− 
Consult hepatologist (unless 
investigator is hepatologist); obtain 
abdominal ultrasound, including 
Doppler assessment of liver 
perfusion; and consider liver biopsy. 
− 
Consider discussing with Clinical 
Study Lead, as needed. 
− 
If investigator suspects toxicity to be 
immune-mediated, promptly initiate 
empiric IV methylprednisolone at 1 
to 2 mg/kg/day  or equivalent. 
− 
If no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been 
done already) and promptly start 
treatment with immunosuppressive 
therapy (e.g., mycophenolate mofetil 
0.5 – 1g every 12 hours then taper in 
consultation with hepatology consult 
or relevant practice guidelines). 
Discuss with study Clinical Lead if 
mycophenolate is not available. 
Infliximabshould NOT be used. 
Isolated AST or 
ALT >20×ULN, 
Permanently discontinue study 
drug/study regimen. 
Same as above 


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Approval date: 05-Jan-2022 
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whether normal 
or elevatedat 
baseline 
(except recommendobtaining liver biopsy 
early) 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, 
infections, recent IV contrast, 
medications, fluid status). 
− 
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). 
− 
Consider using steroids 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: 
− 
Monitor serum creatinine weekly and 
any accompanying symptoms. 
• 
If creatinine returns to 
baseline, resume its regular 
monitoring per study 
protocol. 
• 
If creatinine worsens, 
depending on the severity, 
treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
Grade 2 
Hold study drug/study regimen 
until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity improves to 
Grade ≤1 or baseline, then 
resume study drug/study 
regimen after completion 
of steroid taper (<10mg 
prednisone or equivalent). 
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 beyond 3 to 5 
days or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, consider additional 
workup. 
− 
When event returns to baseline, 
resume study drug/study regimen and 
routine serum creatinine monitoring 
per study protocol. 


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Grade 3 or 4 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine 
on daily basis. 
− 
Consult nephrologist and consider 
renal biopsy if clinically indicated. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should 
be considered and prompt treatment 
with an immunosuppressive in 
consultation with a nephrologist. 
Rash or Dermatitis 
(including Pemphigoid) 
Any Grade 
(refer to NCI 
CTCAE 
applicable version 
in study protocol 
for definition of 
severity/grade 
depending on type 
of skin rash) 
General Guidance 
For Any Grade: 
− 
Patients should be thoroughly 
evaluated to rule out alternative 
etiology. 
− 
Monitor for signs and symptoms of 
dermatitis (rash and pruritus). 
− 
Hold study drug if Stevens-Johnson 
Syndrome (SJS), Toxic Epidermal 
Necrolysis (TEN), or other severe 
cutaneous adverse reaction (SCAR) is 
suspected 
− 
Permanently discontinue study drugs 
if SJS, TEN or SCAR is confirmed 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., emollient, 
lotion, or institutional standard). 
Grade 2 
For persistent (>1 week) 
Grade 2 events, hold scheduled 
study drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
• 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume drug/study 
regimen after completion 
of steroid taper (<10mg 
prednisone or 
equivalent). 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, 
including oral antipruritics (eg, 
diphenhydramine or hydroxyzine) 
and topical therapy. 
− 
Consider moderate-strength topical 
steroid. 
− 
If no improvement of rash/skin 
lesions occurs within 3 to 5 days or is 
worsening despite symptomatic 
treatment and/or use of moderate 
strength topical steroid, discuss with 
Clinical Study Lead, as needed, 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 week or recurs. 
Grade 3 or 4 
For Grade 3: 
For Grade 3 or 4: 


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Hold study drug/study regimen 
until resolution to Grade ≤1 or 
baseline. 
− 
If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume drug/study 
regimen after 
completion of steroid 
taper (<10mg 
prednisone or 
equivalent). 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of 
Nines]. 
− 
Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
Consider, as necessary, discussing 
with Clinical Study Lead. 
Endocrinopathy 
(eg, 
hyperthyroidism, 
thyroiditis, 
hypothyroidism, 
Type 1 diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency) 
Any Grade 
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression 
including brain metastases, or 
infections). 
− 
Consider consulting an 
endocrinologist for endocrine events. 
− 
Consider discussing with Clinical 
Study Lead, as needed. 
− 
Monitor patients for signs and 
symptoms of endocrinopathies. Non- 
specific symptoms include headache, 
fatigue, behavior changes, changed 
mental status, photophobia, visual 
field cuts, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, 
polyuria, hypotension, and weakness. 
− 
Depending on the suspected 
endocrinopathy, monitor and evaluate 
thyroid function tests: TSH, free T3 
and free T4 and other relevant 
endocrine labs (e.g., blood glucose 
and ketone levels, hemoglobin A1c 
(HgA1c). If a patient experiences an 
AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or diabetes 
insipidus), the investigator should 
send a blood sample for appropriate 
autoimmune antibody testing. 
− 
Investigators should ask subjects with 
endocrinopathies who may require 
prolonged or continued hormonal 
replacement, to consult their primary 
care physicians or endocrinologists 
about further monitoring and 
treatment after completion of the 
study. 
Grade  1 
No dose modifications. 
For Grade 1: 
− 
Monitor patient with appropriate 
endocrine function tests. 


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− 
For suspected 
hypophysitis/hypopituitarism, 
consider consultation of an 
endocrinologist to guide assessment 
of early-morning ACTH, cortisol, 
TSH and free T4; also consider 
gonadotropins, sex hormones, and 
prolactin levels, as well as 
cosyntropin stimulation test (though 
it may not be useful in diagnosing 
early secondary adrenal 
insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × 
ULN or consistently out of range in 2 
subsequent measurements, include 
free T4 at subsequent cycles as 
clinically indicated and consider 
endocrinology consult. 
Grade 2, 3, or 4 
For Grade 2 endocrinopathy 
other than hypothyroidism and 
type 1 diabetes mellitus 
(T1DM), consider holding 
study drug/study regimen dose 
until patient is clinically stable. 
Study drug/study regimen can 
be resumed once event 
stabilizes and after completion 
of steroid taper (<10mg 
prednisone or equivalent). 
Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(e.g., adrenal insufficiency) 
can be retreated with study 
drug/study regimen  if the 
patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement. 
For Grade 2, 3, or 4: 
− 
Consult endocrinologist to guide 
evaluation of endocrine function and, 
as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
− 
For all patients with abnormal 
endocrine work up, except those with 
isolated hypothyroidism or Type 1 
DM, and as guided by an 
endocrinologist, consider short term 
corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) 
and prompt initiation of treatment 
with relevant hormone replacement. 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
(DM) may be treated with 
appropriate diabetic therapy, without 
corticosteroids. Only hold study 
drug/study regimen in setting of 
hyperglycemia when diagnostic 
workup is positive for diabetic 
ketoacidosis. 
− 
For patients with normal endocrine 
workup (laboratory assessment or 
MRI scans), repeat laboratory 
assessments/MRI as clinically 
indicated. 
Neurotoxicity 
(to include but not be 
limited to non-infectious 
meningitis, non- 
infectious encephalitis 
and autonomic 
neuropathy, excluding 
Myasthenia Gravis and 
Guillain-Barre) 
Any Grade 
(depending on the 
type of 
neurotoxicity, 
refer to NCI 
CTCAE v4.03 for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule 
out any alternative etiology (eg, 
disease progression, infections, 
metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms 
(headache, nausea, vertigo, behavior 
change, or weakness). 


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− Consider appropriate diagnostic 
testing (eg, electromyogram and 
nerve conduction investigations). 
− 
Perform symptomatic treatment with 
neurology consult as appropriate. 
− 
For transverse myelitis, permanently 
discontinue for any grade. 
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. 
Permanently discontinue study 
drug/study regimen if Grade 2 
imAE does not resolve to 
Grade ≤1 within 30 days. 
For Grade 2: 
− 
Consider discuss with the Clinical 
Study Lead. 
− 
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 2 to 3 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 or other 
immunosuppressive depending on the 
specific imAE). 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing 
with Clinical Study Lead. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 
− 
If no improvement within 2 to 3 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(eg, IV IG or other 
immunosuppressive depending on the 
specific imAE). 
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 


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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 neurology 
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. 
− 
It is important to consider that the use 
of steroids as the primary treatment 
of Guillain-Barre is not typically 
considered effective. Patients 
requiring treatment should be started 
with IV IG and followed by 
plasmapheresis if not responsive to 
IV IG. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider discussing with the Clinical 
Study Lead, as needed. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as 
described above. 
− 
Consult a neurologist. 
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: 
− 
Consult a neurologist. 
− 
Consider discussing with the Clinical 
Study Lead, as needed. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as 
described above. 
− 
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 


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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. 
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. 
o Avoid medications that can 
worsen myasthenia gravis 
(e.g. some antibiotics, beta 
blockers, calcium channel 
blockers, muscle relaxants). 
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 or 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Consider discussing with the Clinical 
Study Lead, as needed. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
neurology 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. 


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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. 
o 
Avoid medications that can 
worsen myasthenia gravis 
(e.g. some antibiotics, beta 
blockers, calcium channel 
blockers, muscle relaxants). 
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. 
Amylase/Lipase 
increased 
Any Grade 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g. disease progression, 
viral infection, concomitant 
medications, substance abuse). 
− 
For modest asymptomatic elevations 
in serum amylase and lipase, 
corticosteroid treatment is not 
indicated as long as there are no other 
signs or symptoms of pancreatic 
inflammation. 
− If isolated elevation of enzymes 
without evidence of pancreatitis, 
continue immunotherapy. 
− 
Assess for signs/symptoms of 
pancreatitis 
− 
Consider appropriate diagnostic 
testing (e.g, abdominal CT with 
contrast, MRCP if clinical suspicion 
of pancreatitis and no radiologic 
evidence on CT) 
− 
Consider other causes of elevated 
amylase/lipase 
− 
If evidence of pancreatitis, manage 
according to pancreatitis 
recommendations 
Grade 1 
No dose modification 
Grade 2, 3, or 4 
In consultation with relevant 
pancreatic specialist consider 
continuing study drug/study 
regimen if no 
clinical/radiologic evidence of 
pancreatitis ± improvement in 
amylase/lipase. 
Acute Pancreatitis 
Any Grade 
General Guidance 
− 
Consider gastroenterology referral 


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Grade 2, 3, or 4 
For Grade 2 or 3 
Hold study drug/study regimen 
dose until resolution to Grade 
≤1. 
If toxicity improves to Grade 
<1 or baseline, then resume 
study drug/study regimen after 
completion of steroid taper 
(<10 mg prednisone, or 
equivalent). 
For Grade 4 
Permanently discontinue study 
drug/study regimen 
− 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO or 
IV equivalent 
− 
IV hydration 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently 
if biopsy-proven immune- 
mediated myocarditis 
− 
The prompt diagnosis of immune- 
mediated myocarditis is important, 
particularly in patients with baseline 
cardiopulmonary disease and reduced 
cardiac function. 
− 
Consider discussing with the Clinical 
Study Lead, as needed. 
− 
Monitor patients for signs and 
symptoms of myocarditis (new onset 
or worsening chest pain, arrhythmia, 
shortness of breath, peripheral 
edema). As some symptoms can 
overlap with lung toxicities, 
simultaneously evaluate for and rule 
out pulmonary toxicity as well as 
other causes (e.g., pulmonary 
embolism, congestive heart failure, 
malignant pericardial effusion). 
Consult a cardiologist early, to 
promptly assess whether and when to 
complete a cardiac biopsy, including 
any other diagnostic procedures. 
− 
Initial work-up should include 
clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram 
(ECHO), monitoring of oxygenation 
via pulse oximetry (resting and 
exertion), and additional laboratory 
work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO 
to assess wall motion abnormalities 
when needed. 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, 
other medications, or infections) 
Grade 2, 3, or 4 
If Grade 2-4 
Permanently discontinue study 
drug/study regimen. 
For Grade 2-4 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IVmethylprednisolone 
2 to 4 mg/kg/day  or equivalent after 
Cardiology consultation has 
determined whether and when to 


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complete diagnostic procedures 
including a cardiac biopsy. 
− 
Supportive care (e.g., oxygen) 
− 
If no improvement within 2 to 3 days 
despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 5 
mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the 
discretion of the treating provider or 
relevant practice guidelines). 
Caution: It is important to rule out 
sepsis and refer to infliximablabel 
for general guidance before using 
infliximab. Infliximabis 
contraindicated for patients who 
have heart failure. 
Myositis/Polimyositis 
Any Grade 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, 
other medications, or infections). 
− 
Monitor patients for signs and 
symptoms of poly/myositis. 
Typically, muscle weakness/pain 
occurs in proximal muscles including 
upper arms, thighs, shoulders, hips, 
neck and back, but rarely affects the 
extremities including hands and 
fingers; also difficulty breathing 
and/or trouble swallowing can occur 
and progress rapidly. Increased 
general feelings of tiredness and 
fatigue may occur, and there can be 
newonset falling, difficulty getting up 
from a fall, and trouble climbing 
stairs, standing up from a seated 
position, and/or reaching up. 
− 
If poly/myositis is suspected, a 
Neurology consultation should be 
obtained early, with prompt guidance 
on diagnostic procedures. 
Myocarditis may co-occur with 
poly/myositis; refer to guidance 
under Myocarditis. Given breathing 
complications, refer to guidance 
under Pneumonitis/ILD. Given 
possibility of an existent (but 
previously unknown) autoimmune 
disorder, consider Rheumatology 
consultation. 
− 
Consider, as necessary, discussing 
with the Clinical Study Lead. 
− 
Initial work-up should include 
clinical evaluation, creatine kinase, 
aldolase, lactate dehydrogenase 
(LDH), blood urea nitrogen 
(BUN)/creatinine, erythrocyte 
sedimentation rate or C-reactive 
protein (CRP) level, urine myoglobin, 
and additional laboratory workup as 
indicated, including a number of 


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possible rheumatological/antibody 
tests (i.e., consider whether a 
rheumatologist consultation is 
indicated and could  guide need for 
rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, 
antisynthetase [such as anti-Jo-1], 
and/or signal-recognition  particle 
antibodies). Confirmatory testing 
may include electromyography, nerve 
conduction studies, MRI of the 
muscles, and/or a muscle biopsy. 
Consider Barium swallow for 
evaluation of dysphagia or 
dysphonia. 
Grade 1 
No dose modification 
− 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms and 
initiate evaluation as clinically 
indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing 
with the Clinical Study Lead. 
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. 
− 
Monitor symptoms daily and consider 
hospitalization. 
− 
Obtain Neurology consult, and 
initiate evaluation. 
− 
Consider, as necessary, discussing 
with the Clinical Study Lead. 
− 
If clinical course is rapidly 
progressive (particularly if difficulty 
breathing and/or trouble swallowing), 
promptly start IVmethylprednisolone 
2 to 4 mg/kg/day  systemic steroids 
along with receiving input from 
Neurology consultant 
− 
If clinical course is not rapidly 
progressive, start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no 
improvement within 2 to 3 days, 
continue additional work up and start 
treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV 
methylprednisolone at 2 to 4 
mg/kg/day there is no improvement 
within 2 to 3 days, consider starting 
another immunosuppressive therapy 
such as a TNF inhibitor (e.g., 
infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating 
provider or relevant practice 
guidelines). Caution: It is important 
to rule out sepsis and refer to 
infliximab label for general guidance 
before using infliximab. 
Grade 3, or 4 
For Grade 3: 
For Grade 3 or 4 
− 
Monitor symptoms closely; 
recommend hospitalization. 
− 
Obtain Neurology consult 


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Hold study drug/study regimen 
dose until resolution to Grade 
≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to 
Grade ≤1 within 30 days or if 
there are signs of respiratory 
insufficiency. 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
− 
Consider discussing with the Clinical 
Study Lead as needed. 
− 
Promptly start IVmethylprednisolone 
2 to 4 mg/kg/day  systemic steroids 
along with receiving input from 
Neurology consultant. 
− 
If after start of IV 
methylprednisolone at 2 to 4 
mg/kg/day  there is no improvement 
within 2 to 3 days, consider starting 
another immunosuppressive therapy 
such as TNF inhibitors (e.g., 
infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating 
provider or relevant practice 
guidelines). Caution: It is important 
to rule out sepsis and refer to 
infliximablabel for general 
guidance before using infliximab. 
− 
Consider whether patient may require 
IV IG, plasmapheresis. 
 
 
Other-Immune-Mediated Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: It is possible that events with an 
inflammatory or immune mediated mechanism 
could occur in nearly all organs, some of them 
are not noted specifically in these guidelines 
(e.g. immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis). 
− 
The Clinical Study Lead may be contacted for 
immune-mediated reactions not listed in the 
“specific immune-mediated reactions” section 
− Thorough evaluation to rule out any alternative 
etiology (e.g., disease progression, concomitant 
medications, and infections) 
− 
Consultation with relevant specialist 
− 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications 
Monitor as clinically indicated 
Grade 2 
• 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
Study drug/study regimen can be 
resumed once event stabilizes to 
Grade ≤1 after completion of steroid 
taper. 
• 
Consider whether study drug/study 
regimen should be permanently 
discontinued in Grade 2 events with 
high likelihood for morbidity and/or 
mortality when they do not rapidly 
improve to Grade ≤1 upon treatment 
with systemic steroids and following 
full taper. 
For Grade 2, 3, or 4 
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and society guidelines 
(e.g., NCCN, ESMO) 
Grade 3 
Hold study drug/study regimen 


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Grade 4 
Permanently discontinue study drug/study 
regimen 


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Table 5 
Infusion-related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the 
discretion of investigator. 
− 
Monitor patients for signs and symptoms of 
infusion-related reactions (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 , appropriate clinical 
practice guidelines, and society guidelines. 


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Table 6 
Non-immune-mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study treatment 
(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. 
Treat accordingly, as per institutional standard. 
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. 
Treat accordingly, as per institutional standard. 
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. 
 
Abbreviations: AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse 
event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease 
Service; ILD = interstitial lung disease; IM = intramuscular; irAE = immune-related adverse event; IV 
= intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; PO = by mouth; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = 
upper limit of normal. 
NOTE: Patients should have ANC >= 1, hemoglobin >= 9 and platelet count >= 100 on cycle 1, 
day 1 (See section 6.1, Subject Inclusion Criteria).  Patients should have ANC >= 1 and platelet 
>= 75 on Day 1 of subsequent cycles (Cycle 2 Day 1 and onward) for retreatment. 
Restrictions during the study and Concomitant treatment(s) 
Restrictions during the study 
Contraception 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use at least one highly effective method of contraception (Table 7) from the time of screening and 


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must agree to continue using such precautions for 180 days after the last dose of durvalumab + 
tremelimumab regimen therapy or 90 days after the last dose of durvalumab monotherapy, 
whichever is the longer time period. Male partners of a female subject must use male condom plus 
spermicide throughout this period. Cessation of birth control after this point should be discussed with 
a responsible physician.  Periodic abstinence, the rhythm method, and the withdrawal method are 
not acceptable methods of birth control. 
 
Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (defined 12 
months with no menses without an alternative medical cause). 
Highly effective methods of contraception are described in Table 7. A highly effective method of 
contraception is defined as one that results in a low failure rate (i.e. less than 1% per year) when 
used consistently and correctly. Note that some contraception methods are not considered highly 
effective (e.g. male or female condom with or without spermicide; female cap, diaphragm, or sponge 
with or without spermicide; non-copper containing intrauterine device; progestogen-only oral 
hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action  
[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 
 
Table 7 
Highly Effectivea Methods of Contraception 
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 
 
 
Permitted concomitant medications 
The Principal Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the CRF. 
Restricted, prohibited,  and permitted concomitant medications are described in the following tables. 
Refer to Section 6.6 for guidance on management of IP-related toxicities. 


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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 below. 
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 palliative radiotherapy), immunotherapy, 
biologic or hormonal therapy for cancer treatment, other than the protocol specified therapies. 
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). 
 
4. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the first 
dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab. 
Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 


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Table 8. 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-L1 
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 
palliativ e 
radiotherapy, etc]) 
Should be used when necessary for all patients 
Best 
supportive 
care 
(including 
 
antibiotics, 
nutritional support, growth factor support, correction 
of metabolic disorders, optimal  symptom  control, 
and 
pain 
management 
[including 
palliativ e 
radiotherapy, etc]) 
Should be used when necessary for all patients 
 
 
Blood donation 
Subjects should not donate  blood while participating  in this study, or for at least 90 days 
following the last infusion of durvalumab or tremelimumab. 


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11.3 
General 
 
It is expected that patients with nausea, emesis, diarrhea, or constipation will receive 
appropriate medical management without dose modification. However, patients with 
persistent (≥ 24 hours) Grade ≥3 toxicity in spite of optimal medical management require 
reduction of one dose level and delay in subsequent therapy for a maximum of 2 weeks until 
recovered to Grade 1. 
Other non-hematologic toxicities with an impact on organ function of Grade ≥2 require delay 
in subsequent therapy for a maximum of 28 days until recovered to Grade 1, or pre-therapy 
baseline. 
Hematopoietic Growth Factors and Blood Products 
 
Erythropoietin, darbepoetin alfa, romiplostim and/or hematopoietic colony-stimulating factors 
for treatment of cytopenias should be administered according to institutional guidelines. 
Transfusion thresholds for blood product support will be in accordance with institutional 
guidelines. 
11.4 
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. 
Safety Parameters 
 
11.4.1 Definition of adverse events 
 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
The International  Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to 
represent a change beyond the range of normal physiologic fluctuation, should be reported 
as an AE. 
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 


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sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition, that did  
not worsen from baseline, is not considered an AE (serious or nonserious). An untoward 
medical event occurring during the prescheduled elective procedure or routinely scheduled 
treatment should be recorded as an AE or SAE. 
 
The term AE is used to include both serious and non-serious AE’s. 
 
11.4.2 Definition of Serious Adverse Events (SAE’s) 
 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect in offspring of the subject 
• 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse. 
The causality of SAE’s (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
11.4.3 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 sponsor. An AESI may be serious or non-serious. 
 
The  rapid  reporting  of  AESIs  allows  ongoing  surveillance  of  these  events  in  order  to 
characterize and understand them in association with the use of this investigational product. 
 
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  regimen  therapy.  An  immune-related  adverse 


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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 etiology. 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. 
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 4. 
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 Section 17.2. 
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-
PD-L1 and anti-PD-1 therapy. 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 


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against the mAbs and serum sickness. Acute allergic reactions may occur, may be severe, 
and may result in death. Acute allergic reactions may include hypotension, dyspnea, cyanosis, 
respiratory failure, urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, 
wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting, and 
unresponsiveness. Guidelines for the management of patients with hypersensitivity (including 
anaphylactic reaction) and infusion-related reactions are provided in Table 4. 
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 
objective evidence that clearly supports causation by a disease (eg, cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the IP. 
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 
4. 
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 4. 
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 4. 
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 4. 
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.) 


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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. Guidelines 
for the management of patients with immune-mediated neurotoxic events are provided in Table 
4. 
11.4.6  Criteria for Hy’s Law (FDA Guidance 2009) 
 
• 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo 
• 
Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of 
serum total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum 
alkaline  phosphatase) 
• 
No other reason can be found to explain the combination of increased aminotransferases 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury. 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Antitumor  Effect 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer, 2009) ]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
 
12.1 
Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment on study. 
Evaluable for objective response. Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease 
reevaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease reevaluated will be considered evaluable 
for non-target disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
12.2 
Disease Parameters 


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Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x- 
ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm 
persistence at least 90 days following completion of radiation therapy. 
 
Malignant  lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only  the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to  further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. The same 
method of assessment and the same technique should be used to characterize each 


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identified and reported lesion at baseline and during followup. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans), but NOT 
lung. 
 
CA125: CA125 alone cannot be used to assess response. If CA125 is initially above the 
upper normal limit, it must normalize for a patient to be considered in complete clinical 
response. 
12.4 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If CA125 is initially above the upper normal limit, it must normalize for a patient to be 
considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
CA125 level above the normal limits. 


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Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment  until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation  criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation  is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented  at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript  for further  details on what is evidence of a new lesion. 
** 
Only for non-randomized  trials with response as primary endpoint. 
*** 
In exceptional circumstances,  unequivocal progression in non-target lesions may be 
accepted as disease progression. 
**** 
. 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without  objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
∗ 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 


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Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal  PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly  used as an endpoint for assessment of efficacy  in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). The 
duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of recurrence, progression, or death, whichever occurs first. 
Survival 
 
Survival is defined as the duration of time from start of treatment to time of death or the date 
of last contact whichever occurs first. 
Permitted Deviations from RECIST 
 
The study's efficacy objectives will be evaluated according to the standard, unmodified 
RECIST v1.1 criteria described in section 12.3, and that, within the context of this protocol, 
the only purpose of the modifications to the criteria is to allow certain patients to continue the 
study treatment despite meeting RECIST criteria for progression of disease. 
 
The response to immunotherapy may differ from the typical responses observed with 
cytotoxic chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• 
Response to immunotherapy may be delayed 
• 
Response to immunotherapy may occur after POD by conventional criteria 
• 
The appearance of new lesions may not represent POD with immunotherapy 
• 
SD while on immunotherapy may be durable and represent clinical benefit. 


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As long as they are receiving treatment on protocol, patients will be permitted to continue 
study treatment after RECIST v 1.1 criteria for POD are met if they meet all of the following 
criteria: 
 
• 
Absence of symptoms and signs indicating unequivocal progression of disease 
• 
No decline in ECOG performance status 
• 
Absence of tumor growth at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
• 
Patients for whom approved therapies exist must provide verbal consent to acknowledge 
deferring these treatment options in favor of continuing study treatment at the time of 
initial apparent progression 
Patients with radiographic disease progression at the at subsequent tumor assessment may 
be considered for continued study treatment at the discretion of the investigator if they 
continue to meet the criteria above and have evidence of clinical benefit. 
Modification of RECIST as described may discourage the early discontinuation of 
durvalumab and tremelimumab and provide a more complete evaluation of its anti-tumor 
activity than would be seen with conventional response criteria.  Nonetheless, the efficacy 
analysis will be conducted by programmatically deriving each efficacy endpoint based on 
RECIST v 1.1 criteria. 
The primary reason for study treatment discontinuation should be documented on the eCRF. 
 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab with or with 
tremelimumab or with symptomatic progression that requires urgent medical intervention 
(e.g., central nervous system metastasis, respiratory failure due to tumor, spinal cord 
compression). 
 
irRECIST 
 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. are presented 
below. irRECIST assessments will only be completed for patients continuing treatment 
beyond PD. 
I. 
Baseline Assessments in irRECIST 
 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1. 
II 
Follow-up Assessments in irRECIST 
 
A. Follow-up recording of target and new measurable lesions 
A key difference in irRECIST is that the appearance new lesions does not 
automatically indicate progression.  Instead, all measured lesions (baseline-selected 
target lesions and new measurable lesions) are combined into the total measured 


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tumor burden (TMTB) at follow up.  Baseline-selected target lesions and new 
measurable lesions are NOT assessed separately. Measurements of those lesions are 
combined into the TMTB, and one combined assessment provided. 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, 
per time point), new lesions must meet criteria as defined for baseline target lesion selection 
and meet the same minimum size requirements of 10 mm in long diameter and minimum 15 
mm in short axis for new measurable lymph nodes. New measurable lesions should be 
prioritized according to size, and the largest lesions elected as new measured lesions. 
 
B. Follow-up non-target assessment 
RECIST 1.1 definitions for assessment of non-target lesions apply.  The response of non- 
target lesions primarily contributes to the overall response assessments of irCR and irNon- 
CR/Non-PD (irNN). Non-target lesions do not affect irPR and irSD assessments. Only a 
massive and unequivocal worsening of non-target lesions alone, even without progress in the 
TMTB is indicative of irPD.  In alignment with RECIST 1.1, baseline selected non-target 
lesions can never convert to measurable lesions, not even if they increase in size at 
subsequent time points and become measurable. Only true new lesions can be measured 
and contribute to the TMTB. 
C. Follow-up for New Non-Measurable Lesions 
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only a massive and unequivocal progression of new 
non-measurable lesions leads to an overall assessment of irPD for the time point. Persisting 
new non-measurable lesions prevent irCR. 
III 
Overall Assessments for irRECIST 
 
The irRECIST overall tumor assessment is based on TMTB of measured target and 
new lesions, non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment (TA), the 
SumD of the target lesions and of new, measurable lesions (up to 2 new lesions per organ, 
total 5 new lesions) are added together to provide the total measurable tumor burden (TMTB). 
 
Overall Assessments  by irRECIST 
Complete 
Response  (irCR) 
Complete disappearance  of all measurable and non-measurable  lesions. Lymph 
nodes must decrease to < 10 mm in short axis. 
Partial Response 
(irPR) 
Decrease of ≥ 30% in TMTB  relative  to baseline, non-target  lesions are irNN, 
and no unequivocal  progression  of new non-measurable  lesions 
• 
If new measurable  lesions appear in subjects with no ta rge t le sions a t 
ba se line, irPD will be assessed. That irPD time point will be considered a 
new baseline, and all subsequent  time points will be compared to it for 
response assessment. irPR is possible if the TMTB  of new measurable 
lesions decreases by ≥ 30% compared to the first irPD documentation 


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Ver. Date: 12/16/20 
 
 
 
• 
irRECIST can be used in the a djuva nt se tting, in subjects with no visible 
disease on CT/MRI  scans. The appearance  of new measurable lesion(s) 
automatically leads to an increase in TMTB  by 100% and leads to irPD. 
These subjects can achieve a response if the TMTB  decreases at follow-up, 
as a sign of delayed response. 
• 
Based on the above, sponsors may consider enrolling subjects with no 
measurable disease and/or no visible disease in studies with response 
related endpoints. 
Stable Disease 
(irSD) 
Failure to meet criteria for irCR or irPR in the absence of irPD 
Progressive 
Disease  (irPD) 
Minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target  or new non-measurable  lesions. . 
• 
In irRECIST a substantial and unequivocal  increase of non-ta rge t le sions is 
indicative  of progression. 
• 
IrPD may be assigned for a subject with multiple ne w non-me a sura ble 
le sions if they are considered to be a sign of unequivocal  massive 
worsening 
Other 
irNE: used in exceptional cases where  insufficient  data exist. 
irND: in adjuvant  setting when no disease is detected 
irNN:, no target disease was identified  at baseline,  and at follow-up  the subject 
fails to meet criteria for irCR or irPD 
 
 
12.5 Biomarker Assessment 
The study will include analyses of archival tumor tissue and peripheral blood to define the 
biomarkers that could predict/correlate with response. Research bloods will be collected pre- 
treatment at 4 pre-specified time points: Day 1, Day 8, Day 29, Day 57, with a window of -3 Days for 
each draw. 6 CPT tubes will be collected at each time point. 
 
12.5.1 Tissue PD-L1 expression (MedImmune) 
The levels of PD-L1 expression in tumor cells and tumor-infiltrating immune cells will be assessed 
using SP263 antibody on archival tissue 
 
12.5.2 Tissue gene expression profiling and IHC (MSKCC, Zamarin, Wolchok lab) 
By using Nanostring nCounter PanCancer Immune Profiling Panel, and immunofluorescence 
microscopy, archival tumor tissue will be assessed for tumor infiltration with various immune cell 
subsets, including CD8 cells, CD4+ effector cells (FoxP3-), CD4+ regulatory T cells (FoxP3+), and 
myeloid cells (CD68+). Tumors will also be assessed for the expression of the known activating co- 
stimulatory receptors such as 4-1BB (CD137), OX40, GITR, CD40, and ICOS, as well as known 
immuneinhibitory components suchas PD-L1, indoleamine dioxygenase (IDO), B7-H3, B7-H4, LAG3, 
TIM-3, PD-1, CTLA-4, VISTA, and BTLA. The expression of each gene will be treated as a continuous 
variable. For exploratory biomarker analyses, patients will be dichotomized on the basis of the primary 
efficacy endpoint. 
 
12.5.3 PBMC immunophenotyping  (MSKCC: IMF) 
 
By using multi-parameter flow cytometry, we will explore whether peripheral blood biomarkers could 
serve as  early  predictors  of clinical benefit and provide targets  for further combinations, with a 
particular focus on targetable markers of T cell activation (ICOS, CD137, OX40, GITR), and inhibition 
(LAG3, TIM3, PD-1, BTLA, VISTA), as well as percentages of peripheral inhibitory immune subsets 
such as MDSCs and Tregs. 


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12.5.4 PBMC gene expression analyses (MSKCC, Zamarin, Wolchok lab) 
RNA extracted from PBMCs collected at baseline and on-treatment will be analyzed on the Nanostring 
platform using Nanostring nCounter PanCancer Immune Profiling Panel, to define gene signatures 
associated with clinical benefit. 
 
12.5.5 PBMC T cell receptor (TCR) repertoire analyses (MSKCC: IMF, Zamarin,  Wolchok lab) 
Maintenance and expansion of particular T cell receptor (TCR) clones in the peripheral blood may 
be associated with clinical response. PBMC¹s collected during the study will be banked for potential 
future TCR repertoire analyses. DNA isolated from PBMC¹s will be send for deep sequencing of 
TCR CDR regions at Adaptive Biotechnologies to determine whether maintenance or emergence of 
particular oligoclonal populations of T cells in the periphery is predictive of clinical benefit. 
12.5.6 Plasma assays 
Plasma collected with PBMCs will be stored for additional analyses. Current PBMC-based assays 
are cumbersome and suffer from variability due to differences in PBMC collection. Plasma-based 
analyses will include analyses of circulating tumor DNA and RNA, multiplex cytokine ELISAs, and 
serologic assays for antibodies to specific tumor-associated antigens. 
 
12.5.7 Future research 
Leftover blood and tissue samples from the study will in addition be stored for future research using 
the assays currently in development, including new single-cell based technologies. The future 
research will continue to be directed towards evaluation of potential novel biomarkers of 
response/resistance to durvalumab and durvalumab/tremelimumab combination. 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. Any patient who withdraws will be encouraged to 
return to the study center for a treatment completion visit. Patients who discontinue early should 
return within 30 days following the final dose of study treatment. The primary reason for 
discontinuation must be recorded in the medical record. 
Permanent discontinuation of treatment with Durvalumab and Tremelimumab 
 
An individual subject will not receive any further investigational product if any of the following occur in 
the subject in question: 
• 
Disease progression, per investigator assessment 
• 
Intolerable toxicity of study drugs 
• 
Withdrawal of consent or lost to follow-up 
 
• 
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further dosing 
 
• 
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 
• 
Pregnancy or intent to become pregnant 
 
• 
Grade ≥ 3 infusion reaction 


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• 
Initiation  of alternative anticancer therapy including another investigational  agent 
Other reasons for patient discontinuation may include, but are not limited to, the following: 
• 
Change in patient eligibility 
• 
Non-compliance 
• 
Patient decision 
• 
If treatment is delayed for more than 28 consecutive days 
• 
Withdrawal of consent 
• 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation. 
• 
The investigator has the right to discontinue a patient from the study for any medical condition 
that the investigator determines may jeopardize the patient’s safety if he or she continues in the 
study; for reasons of noncompliance (e.g., missed doses, visits); or if the investigator determines 
it is in the best interest of the patient. 
14.0 
BIOSTATISTICS 
 
This Phase 2 study aims to assess the activity of Durvalumab alone and in combination with 
Tremelimumab in patients with recurrent or persistent endometrial carcinomas or endometrial 
carcinosarcomas. Patients will be randomized to Arm 1: Durvalumab (anti-PD-L1 Antibody) alone or 
Arm 2: Durvalumab with Tremelimumab (anti-CTLA-4 antibody). This is a randomized study 
however it is not powered to show superiority of one arm versus another. 
 
In this study, all analyses will be performed by treatment arm. 
To date, there are no published studies of immune checkpoint inhibitors in this patient population. 
 
Extrapolating from prior monotherapy studies of immune checkpoint inhibitors in ovarian cancer 
have yielded overall response rates in the range of 10-15%, and may serve as a basis for historical 
comparison of the doublet tested here. 
Study 
N 
ORR (CR+PR) 
DCR  (ORR+SD) 
Prior Therapy 
Nivolumab  (anti-PD-1) 
1 mg/kg q 2 weeks (cohort 1) 
3 mg/kg q 2 weeks (cohort 2) 
10 
10 
15% (3/20): 
10% (1 PR) 
20% (2 CR) 
50% (5 SD +1 PR) 
40% (2 SD +2 CR) 
≥ 2 priors 
Platinum 
Resistant 
Avelumab  (anti-PD-L1) 
Phase Ib expansion cohort 
10 mg/kg q 2 weeks 
75 
10.7% (8 PR) 
55% (33 SD +8 PR) 
med 4 priors(1-11) 
Platinum 
Resistant 
Pembrolizumab (anti-PD-1) 
Phase Ib expansion cohort 
10 mg/kg q 2 weeks 
26 
11.5% (1 CR, 2 
PR) 
35% (9 SD+1CR+2 
PR) 
>80% > 4 priors 
PD-L1+ (IHC) 
 
 
ORR (defined as CR+PR) will be the primary endpoint. A 10% ORR will be considered low and 25% 
or higher will be considered promising for further studies. Forty patients provide 90% power and 
Type I error of 10% using a Simon two stage minimax design. There will be an interim analysis after 
evaluable 27 patients and if 3 or more responders (CR+PR) are observed out of evaluable 27 
patients then the study will continue to the second stage. At the end of the study we require 7 or 
more responders out of 40 patients to  declare this study positive and the arm worthy for further 
investigation. 
 
Unacceptable response rate:  0.1 


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Desirable response rate:  0.25 
Error rates: Type I =  0.1 ; Type II = 0.1 
 
# 
responses 
required 
in Stage I 
# patients 
accrued 
at stage I 
# 
responses 
required 
in Stage 2 
Total 
sample 
size 
>=3 
27 
>=7 
40 
 
 
If the test for ORR is significant, then the PFS rate at 24 weeks (+/- 1 week) will also be tested 
against the historical control estimate. For PFS rate at 24 weeks (+/- 1 week), we consider a 15% 
rate as low, and a rate of 35% or higher as indicative of promising activity. This stems from 
Gynecologic Oncology Group studies of the same patient population we are evaluating in this study 
which have deemed PFS at 6 months of 15% or less as indicative of lack of activity and PFS at 6 
months of 35% or more as indicative of having activity. 
This test of PFS rate will be performed only if the ORR analysis is significant, and thus PFS 
assessment is supplementary to ORR assessment. At the end of the study, if 10 or more out of 40 
patients are considered progression free at 24 weeks (+/- 1 week), then that arm  will be considered 
worthy of further study. This study will have 94% power and 7% Type I error to show activity in terms 
of 6 months PFS rate. The overall Type I error of the study is bounded by the 10% error rate of the 
first hypothesis of ORR. The hierarchy in the two hypotheses for ORR and PFS ensures the overall 
error rate to be smaller than 10% (Bretz 2009) 
 
If both arms have >=7 responders the winning arm is the one with higher ORR and if both arms have 
exactly 7 responders the winning arm will be decided based on the review of all efficacy data (ORR 
and PFS) and the total safety profile (number and type of grade 3 AE) of each arm. 
A treatment arm will be considered promising if the ORR decision rule is met, but the 6 month PFS 
decision rule is not met. After first stage accrual is complete, we will halt the study for 16 weeks after 
last patient has been accrued to first stage in order to assess the decision rules to move to stage 2. 
Based on historical accrual rates in similar populations, we anticipate successful enrollment of 4 
patients per month yielding a total accrual time of 20 months. Accrual will continue until 40 patients 
on each arm(evaluable patients are defined in section 12.1), unless the interim analysis after 27 
patients does not support continuation. 
 
 
 
 
 
Definitions of Statistics to be Reported 
 
• 
Clinical Benefit Rate (CBR)), defined as the percentage of patients with complete response (CR) 
+ partial response (PR) + stable disease (SD) by 24 weeks from the start of treatment will be 
reported and the 90% confidence interval will be estimated using exact binomial proportions . 
This will be done following RECIST criteria. 
• 
Progression free survival (PFS), defined as the duration of time from start of treatment to time of 
recurrence, progression, or death due to any cause, whichever occurs first. Patients will be 
censored at last follow up date. The Kaplan Meier estimate of median PFS will be reported as 
well as the PFS rate at 24 weeks(+/- 1 week). 
• 
Duration of response (DOR), defined as the time from which measurement criteria are met for 
CR or PR (whichever status is recorded first using RECIST) until the first date of documented 


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disease progression, will be estimated using the Kaplan Meier method. Patients without 
documented progression will be censored at last follow up. 
• 
The rate of response using immune response criteria (refer to irRECIST description in section 
12.3, which defines responders and non responders) and the 90% confidence interval will be 
estimated using exact binomial proportions. 
• 
Adverse events by the current version of Common Terminology Criteria for Adverse Events 
version 4 (CTCAE v4.03) will be tabulated in order to assess the safety profile and tolerability 
therapy in treated patients. 
 
Safety Analysis 
 
The frequency and severity of observed adverse effects will be evaluated. 
The rates of irAE, SAE, therapy completion rate, and protocol completion will also be reported. 
 
Safety will be measured by the frequency of grade 3 or 4 treatment-related clinically significant 
toxicities (NCI Common Terminology Criteria for Adverse Events version 3.0), aside from Grade 3 or 
4 hematologic or laboratory abnormalities, unless they are deemed unexpected or clinically 
significant. 
  
Frequencies of toxicities will be tabulated. The grade 3 or 4 treatment-related non-hematologic/non- 
laboratory toxicity will be estimated at the end of the trial along with the 95% confidence interval. 
With 40 patients per arm, these rates can be estimated within ±16%. 
 
 
Methods of Efficacy Analysis 
Efficacy Variables 
The intent of this protocol is to assess checkpoint inhibitors for activity in patients with carcinomas 
advanced, recurrent endometrial carcinomas and carcinosarcomas. 
 
The principal parameters employed to evaluate the efficacy of the two arms are: 
• 
The rate of ORR and duration of overall objective response (ORR = CR + PR). 
 
• 
Progression-free survival rate at 24 weeks for all patients evaluable for this endpoint. 
 
• 
Clinical Benefit Rate (CBR) will be defined as ORR + Stable Disease (SD) rate by 24 
weeks. 
 
Patients who have measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease reevaluated will be considered evaluable for response and PFS. 
The primary efficacy analysis will include only patients who are evaluable for response. Patients 
without post baseline assessment of response will be included in a sensitivity analysis as non 
responders for ORR, and events for PFS. A 90% confidence interval for PFS will also be provided. 
 
 
All patients will be followed up for a minimum of 6 months. We do not expect any patient to have a 
follow up of less than 6 months. If a patient meets all the criteria for being evaluable but has not 
been followed for 6 months and has not progressed, this patient will be censored at the time of last 
follow up. This patient will be included in the analysis.  For the determination of the decision rule for 
PFS (ie >=10 patients event free), this patient will be considered a failure. 


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For safety, all patients who received at least one cycle of therapy will be included. 
 
 
As per the standard of reference set by the Gynecologic Oncology Group for recurrent endometrial 
cancers, if a new agent has a true response rate of 10% or less, it would be considered of little 
clinical significance. Conversely, if the true response rate is at least 25%, further investigation is 
clearly indicated. These are the reference ORR numbers used to assess novel agents in the GOG- 
129 and 229 queue, through which nearly 20 treatments have been evaluated. As a means of 
comparison, and to further justify this ORR goal, the clinical data for several relevant cytotoxic and 
biologic agents are tabulated here. 
 
Rx 
ORR 
(%) 
[PR + 
CR] 
PFS at 
24 
weeks 
(%) 
# of 
Patients 
(n) 
Reference 
Etoposide 
0 
8.0 
25 
Rose et al, Gynecol 
Oncol 1996 
Paclitaxel 
25 
20.8 
48 
Ball et al, Gynecol 
Oncol,  1996 
Doxorubicin 
9.3 
23.3 
43 
Thigpen et al, 
Cancer Treat Rep. 
1979, 
Ixabepilone 
12 
20.4 
49 
Dizon et al, JCO, 
2009 
Bevacizumab 
17 
41.5 
53 
Aghajanian et al, 
JCO, 2011 
 
Given the inherent difficulty in detecting meaningful overall survival (OS) data in patients who will 
likely frequently receive multiple, and divergent downstream agents after end of study, including 
possible enrollment in additional clinical trials, PFS at 24 weeks (6 months) is considered an 
appropriate endpoint for meaningful clinical efficacy. (Sill 2008) This approach has been adopted for 
recurrent and advanced endometrial cancer. 
 
 
Exploratory objectives: For exploratory biomarker analyses, patients will be dichotomized on the 
basis of clinical benefit (CBR) rate (CR+PR+SD) as the outcome measure. Exploratory endpoints  
will be analyzed by treatment arm. All biomarkers without known cutoffs will be treated as  
continuous variables For tissue based biomarkers, CBR will be correlated to the level of tissue 
expression of PD-L1 (binary: positive vs negative), or specific genes/gene signatures identified from 
transcriptional profiling. Non parametric 2 sample tests will be used to assess differences in the 
distribution of markers between the 2 groups (responders vs non responders). Archival tumor tissue 
IHC will be assessed only at baseline while other markers will be assessed at baseline and during 
treatment and their change from baseline will be analyzed. For markers such as  number of 
infiltrating CD8+ cells and change in ICOS level expression on lymphocytes from baseline levels, we 
do not have established cutoffs, thus we will examine them as continuous variables. In these 
biomarkers we will look at changes from baseline to treatment (focused on early changes or  
changes within 8-12 weeks), and we explore these changes graphically in order to assess potential 
relationships between responders and non responders. 


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15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria.Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures.During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist.The individual  signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
15.3 
Randomization 
 
Patients will be randomized to Arm 1: Durvalumab (anti-PD-L1 Antibody) alone or Arm 2: 
Durvalumab with Tremelimumab (anti-CTLA-4 antibody). Randomization will be 
accomplished by the method of random permuted block, and patients will be stratified by 
histology( stratum 1: endometrial carcinosarcoma patients or MSI-high  endometrial 
carcinoma patients and stratum 2 :other histologies ). We will limit enrollment of stratum 1 to 
10 patients per arm. 
15.2 
Randomization 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A research study assistant (RSA) will be assigned to study. The responsibilities of the RSA 
include project compliance, data collection, extraction and data entry, data reporting, 
coordination of the activities of the protocol study team and, and of the flow of regulatory 
paperwork. 
The data collected for the study will be entered into a secure database ( MediData RAVE). 
All routine blood test results required per the protocol will be captured in MediData RAVE in 
addition to  baseline medical conditions and disease information, response assessments, off- 
study documentation, and toxicity grade and attribution. Source documentation will be 
available to support the computerized patient record. 
MSKCC will hold the IND and will be responsible for all safety monitoring. All SAEs will be 
reported to the MSKCC IRB. The safety of the study will be monitored by the MSKCC Data 
and Safety Monitoring  Committee. 
Weekly registration reports will be generated by the RSA and reviewed by the PI to monitor 
patient accruals and completeness of registration data. Routine data quality reports will be 
generated to assess missing data and inconsistencies. 
Accrual rates and extent and accuracy of evaluations and follow up will be monitored 
periodically throughout the study. Recurrent lapses in data collection, deviations or violations 
will be discussed with the study team and a corrective plan will be generated. Accrual goals 


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and factors impacting accrual goals will be discussed at the weekly New Patient/Protocol 
meetings. 
If accrual proceeds more quickly than anticipated, it may be slowed or staggered at the 
discretion of the Principal Investigator, to account for safety concerns or data management 
resources. 
16.2 
Quality Assurance 
 
The Principal Investigator  is responsible for ensuring that all staff involved  in the study is 
familiar with the content of this section. 
The data and safety monitoring plan at Memorial Sloan Kettering Cancer Center was 
approved by the National Cancer Institute in September 2001. The plan addressed the new 
policies set forth by the NCI and the document entitled "Policy of the National Cancer  
Institute for data and safety monitoring of clinical trials" which can be found at 
http://grants.nih.gov/grants/guide/noticefiles/not98-084.html.  The DSM plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC data and 
safety monitoring plan can be found on the MSKCC Internet at 
http://inside2/clinresearch/Documents/MSKCC Data and Safety Monitoring  Plans.pdf. There 
are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff  
education on clinical research QA) and departmental procedures for quality control, plus  
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. Memorial Sloan Kettering Cancer Center has set up three distinct 
monitoring processes for our clinical trials program. There are two sub-committees that have 
the responsibility of data and safety monitoring. These are joint sub-committees with dual- 
reporting responsibilities. The Data and Safety Monitoring  Committee (DSMC) is the sub- 
committee responsible for monitoring all Phase 1, 2, 1/2, pilot and non-phase clinical trials. 
The Data and Safety Monitoring Board (DSMB) is the sub-committee responsible for 
monitoring Phase 3 randomized clinical trials. The Therapeutic Response Review Committee 
(TRRC) is the sub-committee of Research Council responsible for the independent 
therapeutic response review for participants in IRB/PB approved clinical trials where 
therapeutic efficacy is a stated primary objective, typically phase 2 and 3 trials. Formal 
monitoring of such studies is designed to ensure that the interests of the  participants are 
being scrutinized on a regular basis, and that the trial is progressing in a satisfactory manner. 
The DSMC convenes once per quarter and monitors the risk participants are exposed to, the 
progress of the study, the adequacy of the data storage and whether sufficient data are being 
entered into the  MediData RAVE. The DSMC monitors phase 1, 2, 1/2, pilot and non-phase 
trials that are not being monitored by an industrial sponsor, and which meet the NCI 
definition of a Clinical Trial. This trial will qualify for monitoring by the DSMC. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required, and the monitoring procedures will be 
established at the time of protocol activation. A detailed description of the data to be 


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collected, process of data collection (i.e., data manager and/or data management office), 
database that will be utilized for data collection and storage (e.g.,  MediData RAVE, user- 
supported software), reporting requirements of the data to the institution (IRB), the sponsor 
and/or governing agency. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The MSKCC 
Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Qualit  
y%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.p   df 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized  de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified  researchers. 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in 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 (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 


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they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 90-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 90-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event.  All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred The adverse event 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form. 
• 
If the SAE is an Unanticipated Problem 
 
For IND/IDE protocols: 
If appropriate, the report will be forwarded to the FDA by the SAE staff through the IND 
Office. 
Ethical conduct of the study 
 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good  Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
17.3.1 Recording of adverse events and serious adverse events 
 
Adverse events will be recorded via Electronic MediData RAVE 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. 


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The following variables will be collected for each AE: 
 
• 
AE (verbatim) 
• 
The date (and time when clinically relevant) 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 durvalumab (yes or no) 
• 
Investigator causality rating against tremelimumab (yes or no) 
• 
Action taken with regard to durvalumab 
• 
Action taken with regard to tremelimumab 
• 
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 
• 
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 durvalumab or tremelimumab 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
17.2.1.1 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, whichever is later). 
During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have PD and will have no further tumor 
assessments. 
 
 
 
 
Date: 
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. 


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17.2.1.2 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 the eCRF. 
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. 
17.2.1.3 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 study 
subjects after the 90-day safety follow-up period for patients treated with Durvalumab or 
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 principal investigator. 
17.2.1.4 Reporting of serious adverse events 
 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period 
immediately following the time that written informed consent is obtained through 90 days 
after the last dose of durvalumab + tremelimumab or until the initiation of alternative 
anticancer therapy.  The investigator is 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 a MedWatch/AdEERs 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 MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is 
reported to the FDA.  It is the responsibility of the sponsor to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at 
the same time. 
 
 
 
 
 
 
 
 
 
 
Date: 
The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs 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 MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is reported 
to the FDA. It is the responsibility of the sponsor to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting requirement timelines 
and to ensure that these reports are also submitted to AstraZeneca at the same time. 


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• 
A cover page should accompany the MedWatch/AdEERs form indicating the 
following: 
• 
“Notification from an Investigator Sponsored Study” 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
o The trial name/title and AstraZeneca ISS reference number (ESR-15-10965) 
* 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 preferably using the MedDRA coding language for serious adverse 
events.  This information should be reported on a monthly basis and under no circumstance 
less frequently than quarterly. 
17.2.1.5 Other events requiring reporting 
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 (see Section 11.4 for contact information). If the overdose results in an AE, 
the AE must also be recorded as an AE (see Section 11.4). Overdose does not automatically 
make an AE serious, but if the consequences of the overdose are serious, for example death 
or hospitalization, the event is serious and must be recorded and reported as an SAE (see 
Section 11.4). 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. 
 
 
 
Hepatic function abnormality 
 
Hepatic function abnormality (as defined in Section 11.4) 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 (see Section 11.4 for contact 
 
Date: 


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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. 
Pregnancy 
 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions  without complications should not be handled as AEs. The 
outcomeof all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but 
no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
 
Pregnancy in a subject who has received investigational product 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 (see Section 17.2.1.4 for 
contact information). 
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to AstraZeneca/MedImmune  Patient Safety. 


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18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
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20.0 
APPENDICES 
APPENDIX A: 
Schedule  of study procedures:  follow-up  for subjects who have completed 
durvalumab  and tremelimumab  treatment  and achieved  disease  control (until 
progression  of disease)  and subjects  who have discontinued  durvalumab  or 
tremelimumab due to toxicity in the absence of progression  of disease 
 
Evaluation 
Time Since Last Dose of Durvalumab 
Day (±3) 
Months (±1 week) 
12 Months and Every 
6 Months 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examination 
X 
Vital 
signs 
(temperature, 
blood 
pressure, pulse) 
X 
Weight 
X 
Urine hCG or serum βhCG 
X 
AE/SAE assessment 
X 
X 
X 
Concomitant medications 
X 
X 
X 
Palliative radiotherapy 
As clinically indicated 
<<World 
Health 
Organisation>> 
<<ECOG>> performance status 
X 
X 
X 
X (and month 
9) 
X 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with 
subjects who refuse to return for 
evaluations and agree to be contacted 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Hematology 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
Thyroid function tests (TSH, and T4)a 
X 
Pharmacokinetic 
assessment, 
if 
applicable 
X 
Immunogenicity 
assessment 
(ADA 
sampling [including ADA neutralising 
antibodies] to identify ADA responses 
in subject circulation), if applicable 
X 
 
X 
sPD-L1 concentration (to assess target 
engagement), if applicable 
X 
Circulating soluble factors (to assess 
cytokines, chemokines, growth factors 
and antibodies against tumor and self 
antigens in circulation), if applicable 
X 


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Schedule  of study procedures:  follow-up  for subjects who have completed 
durvalumab  and tremelimumab  treatment  and achieved  disease  control (until 
progression  of disease)  and subjects who have discontinued  durvalumab  or 
tremelimumab due to toxicity in the absence of progression  of disease 
 
Evaluation 
Time Since Last Dose of Durvalumab 
Day (±3) 
Months (±1 week) 
12 Months and Every 
6 Months 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
miRNA/mRNA (to examine immune 
cell 
gene 
expression 
profiles 
in 
circulation), if applicable 
X 
PBMCs, if applicable 
X 
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 PD. 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, then 
every 12 weeks until PD. For patients who remain progression free 2 years post completion 
of protocol directed treatment, every 6 months +/- 1 month. Upon PD, scans should be 
conducted according to local standard clinical practice and submitted for central review until 
a new treatment is started (these scans are optional). 
 
a 
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. 


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Appendix  B. Durvalumab  DOSE VOLUME  CALCULATIONS 
For durvalumab  fixed  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 
Appendix  C. Tremelimumab  DOSE VOLUME  CALCULATIONS 
For tremelimumab  fixed 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: 


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Ver. Date: 12/16/20 
 
 
 
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 
 
APPENDIX D  Biomarkers 
 
Archival tissue will be obtained for analysis of primary tumor. 10-20 unstained PPFE slides 
will be sought from each patient: Half will go to the sponsor, and the remaining ones will 
remain at MSK. A patient will be required to have a minimum of 10 unstained PPFE slides to 
be eligible. No biopsy will be performed for procurement of tissue for purposes of meeting 
eligibility. 
 
• 
AZ/MEDI  will perform assays of PD-L1 expression. 
• 
MSKCC/Zamarin will perform assays for Immunologic markers. 
 
Research bloods will be collected on Day 1, Day 8, Day 29, and Day 57 with a window of -3 Days 
for each draw. 6 CPT tubes will be collected at each time point (all 6 tubes will remain at MSK). 
 
Research Blood Sample Collection Instructions: 6 CPT tubes will be collected on Day 1, Day 8, 
Day 29, and Day 57. 
 
1. Invert all tubes several times immediately after collection to ensure mixing with anticoagulant 
(or clotting activators for serum collection tubes).  For serum tubes, allow blood in tube to clot 
for 30 min at room temperature in a vertical position in a tube rack. 
2. Include patient initials, MRN, date, and time of collection on adhesive stickers attached to 
each tube. 
3. Fill in date and time of collection in requisition form. 
4. Place all collected tubes in a biohazard ziplock bag at room temperature. 
5. Send all specimens via Stat Messengers to Immune Monitoring Core located at the MSKCC 
Zuckerman Research Center (417 E. 68th St, New York, NY), Room 1513. Place into blood 
bin on benchtop. 
6. Notify IMF staff of sample delivery