Clinical trial NCT04989218
Conditions: Cholangiocarcinoma
Keywords: Durvalumab Tremelimumab Platinum-based chemotherapy Gemcitabine Cisplatin
Sponsor: University of Alabama at Birmingham
Start date: 2023-01-30; Completion date: 2024-05-01
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot trial will be used to assess the activity, safety and feasibility of doublet immunotherapy and platinum-based chemotherapy in resectable intrahepatic cholangiocarcinoma with high risk features. The hypothesis is that the combination of durvalumab/MEDI4736 and tremelimumab (doublet immunotherapy) with platinum-based chemotherapy (gemcitabine and cisplatin) will yield an objective of 52% and improve complete resection rates in intrahepatic cholangiocarcinoma. This will facilitate margin negative resection and ultimately reduce recurrence rates and improve survival. Carrying out this trial in the neoadjuvant setting potentially allows improved overall survival and also provides an opportunity for discovery of biomarkers that may predict response to therapy.

Detailed description:
All enrolled participants will receive the study intervention. Patients will receive up to 4 cycles of interventional agents prior to surgical resection. They will undergo imaging scans after the 2nd and 4th cycle (before surgery) of intervention agents. The short interval of scans (6 weeks) allows investigators to identify non responders. These patients may be encouraged to come off study and be treated based on the treating oncologist's choice. Since the investigational agents include 'standard of care' agents, a good argument can be made that these patients would not have benefitted from standard therapy only. Patients with at least stable disease after the 2nd treatment cycle will proceed with study interventions. However, patients with radiologic progression but who remain clinically stable may be allowed to continue treatment if the patient elects to, pending confirmation of progression and after a discussion between the investigator and sponsor-investigator.

Arms: arm 1: This study has one arm. All enrolled patients will receive a combination of a platinum based chemotherapy regimen (gemcitabine and cisplatin) and a combination of two immune check point inhibitors, anti- CTLA4 (Tremelimumab) and anti PDL-1 (durvalumab).

Gemcitabine will be administered (gemzar) intravenously, 1000mg/m2 on Day 1 and Day 8 of a 21 day cycle for up to 4 cycles. Cisplatin (Platinol) will be administered intravenously, 25mg//m2 on Day 1 and Day 8 of a 21 day cycle for up to 4 cycles.

Tremelimumab will be administered intravenously, 300mg flat dose, on Day 1 of cycle 1 only. Durvalumab will be administered intravenously 1500mg on Day 1 of a 21 day cycle for 4 cycles.
Interventions: intervention 1: Novel combination of chemotherapy and immunotherapy
Intervention descriptions: intervention 1: This is a study of the combination of platinum based chemotherapy (gemcitabine and cisplatin) and doublet immunotherapy (durvalumab and tremelimumab) in the preoperative setting for intrahepatic cholangiocarcinoma with high risk features. Gemcitabine and cisplatin are chemotherapy agents used in the management of locally advanced and metastatic cholangiocarcinoma. Durvalumab is a programmed cell death ligand 1 (PDL1) blocking antibody, that improves the immune response against cancer. Tremelimumab is an antibody that targets cytotoxic T cell lymphocyte-associated protein 4 (CTLA4) on regulatory T cells. It also improves the immune response against cancer cells

Protocol documents:
Prot_SAP_000.pdf: 
NCT 04989218 
An open-label window of opportunity trial to evaluate the activity of durvalumab 
(MEDI4736) and tremelimumab with platinum-based chemotherapy (Gemcitabine and 
Cisplatin) in intrahepatic cholangiocarcinoma (ICC) 
Document date: July 19, 2022 


 
 
 
An open-label window of opportunity trial to evaluate the activity of durvalumab 
(MEDI4736) and tremelimumab with platinum-based chemotherapy (Gemcitabine and 
Cisplatin) in intrahepatic cholangiocarcinoma (ICC) 
 
 
Sponsor Investigator 
 Mehmet Akce, MD 
 
Co-Investigators 
Olumide Gbolahan, MD (Emory University Winship Cancer Institute) 
Richard Kim, MD (Moffit Cancer Center) 
Jason Denbo, MD (Moffit Cancer Center) 
Bassel El-Rayes, MD (University of Alabama, Birmingham) 
Sameer Al Diffhala (University of Alabama, Birmingham) 
John Bart Rose, MD (University of Alabama, Birmingham) 
Sushanth Reddy, MD (University of Alabama, Birmingham) 
Grant William, MD (University of Alabama, Birmingham) 
Darryl Outlaw, MD (University of Alabama, Birmingham) 
Ursa Brown-Glaberman, MD (University of New Mexico) 
Itzhak Nir, MD (University of New Mexico) 
Ben Ferguson, MD (University of New Mexico) 
 
 
 
 
Statistician 
Kim Young-il, PhD (University of Alabama, Birmingham) 
 
 
Trial Supported by 
AstraZeneca ESR-19-20173 
 
Investigational New Drug (IND) # 154851   
 
 
 
 
Initial Protocol Version Date: 27AUG2020 
Protocol Amendment Version Date: 04APR2022 
Protocol Amendment Version Date: July 19, 2022 
 
 
 


 
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PROTOCOL SIGNATURE PAGE 
 
An open-label, window of opportunity trial to evaluate the activity of 
durvalumab/MEDI4736 (Durva) and tremelimumab (Trem) with platinum-based 
chemotherapy (Gemcitabine and Cisplatin/GemCis) in intrahepatic cholangiocarcinoma 
(ICC) 
 
VERSION DATE:   July 19, 2022 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
____________________________________ 
________________________ 
Signature of Site Investigator  
 
 
  
Date 
 
 
____________________________________ 
Site Investigator Name (printed) 
 
 
____________________________________ 
Site Investigator Title 
 
 
____________________________________ 
Name of Facility 
 
 
____________________________________ 
Location of Facility (City and State) 
 
 
 
 
 
 
 


 
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SYNOPSIS 
TITLE 
An open-label, window of opportunity trial to evaluate the activity 
of durvalumab/MEDI4736 (Durva) and tremelimumab (Trem) 
with 
platinum-based 
chemotherapy 
(Gemcitabine 
and 
Cisplatin/GemCis) in intrahepatic cholangiocarcinoma (ICC) 
SHORT TITLE 
Durvalumab 
and 
tremelimumab 
with 
platinum-based 
chemotherapy in intrahepatic cholangiocarcinoma 
PHASE  
Window of opportunity trial 
OBJECTIVES 
Primary Objective 
determine the activity of the combination of platinum-based 
chemotherapy (GemCis) combined with doublet immunotherapy 
(Durva/Trem) 
in 
‘borderline 
resectable’ 
intrahepatic 
cholangiocarcinoma 
 
Secondary Objectives 
• Assess the feasibility of neoadjuvant platinum-based 
chemotherapy (GemCis) and doublet immunotherapy for 
high-risk but technically resectable (borderline resectable) 
intrahepatic cholangiocarcinoma. 
• Determine the safety of the combination of platinum-based 
chemotherapy (GemCis) and doublet immunotherapy 
(Durva/Trem) in borderline resectable intrahepatic 
cholangiocarcinoma 
• Determine feasibility of enrolling patients into a large 
Phase II/III trial of ICC. 
 
Exploratory Objectives 
Evaluate blood and tumor-based biomarkers that may be 
associated with improved ORR to combination of platinum-based 
chemotherapy 
(GemCis) 
and 
doublet 
immunotherapy 
(Durva/Trem) 


 
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KEY ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
Inclusion Criteria: 
• Histologically/cytologically 
confirmed 
diagnosed 
intrahepatic cholangiocarcinoma 
• Male or female, from age 18 years of age 
• Body weight >30 kg  
• Measurable disease based on RECIST 1.1 and have 1 or 
more radiologic features compatible with high risk (for 
resection and recurrence) but still considered technically 
surgically resectable by a multidisciplinary tumor board 
• Performance status of 0 or 1 on the ECOG performance 
scale within 3 days prior to 1st dose of study intervention 
• Adequate organ and marrow function 
 
Exclusion Criteria: 
• Previous 
systemic 
therapy 
for 
intrahepatic 
cholangiocarcinoma  
• Ampullary cancer, extrahepatic cholangiocarcinoma and 
gall bladder cancer 
• Any other histologic subtype except adenocarcinoma or 
mixed histology with adenocarcinoma/hepatocellular 
carcinoma.  
• Inflammatory bowel disease (ulcerative colitis or Chron’s 
Disease), or primary sclerosing cholangitis  
STATISTICAL 
CONSIDERATIONS 
 
This is an open-label, window of opportunity, multicenter trial to 
determine the activity and safety of the combination of platinum-
based chemotherapy (gemcitabine and cisplatin) with doublet 
immunotherapy (Durva/Trem) as preoperative therapy in patients 
with histologically and radiologically documented borderline 
resectable intrahepatic cholangiocarcinoma. The study will plan to 
enroll 20 patients across 4 centers over a 2-year period. It is 
estimated that each center will enroll 2 patients per year.  
 
This would potentially be the first part of a larger Phase II trial. 
Borderline resectable ICC makes up only about 20% of ICC which 
on its own is a rare entity. Accruing patients to a relatively large 
trial will be challenging. Limiting the sample size to 20 across 4 
centers allows us to determine the feasibility of recruiting for a 
larger (Phase II or III) study and provides insights for designing 
larger studies. In addition, a key objective of this trial is to obtain 
correlative 
biomarkers 
to 
assess 
the 
effect 
of 
chemoimmunotherapy on the immune milieu of ICC.  
 
The above trial design allows us to explore clinical (radiologic), 
molecular response (RNA expression patterns) and immunologic 
response to 2 or more cycles of chemo-immunotherapy.   


 
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Patients will receive durvalumab 1500mg by intravenous (IV) 
infusion on Day 1 every 3 weeks for up to a maximum of 4 cycles. 
Patients will also receive tremelimumab 300mg on Day 1 on the 
first cycle of treatment only. Additionally, patients will receive 
standard of care chemotherapy with gemcitabine 1000mg/m2 and 
cisplatin 25mg/m2 by IV infusion on Day 1 and Day 8 every 3 
weeks for up to a maximum of 4 cycles.    
 
The combination of Durvalumab/MEDI4736 and Tremelimumab 
(doublet immunotherapy) with platinum-based chemotherapy will 
yield an objective of 52% and improve complete resection rates in 
intrahepatic cholangiocarcinoma. This will facilitate margin 
negative resection and ultimately reduce recurrence rates and 
improve survival. Carrying out this trial in the neoadjuvant setting 
provides an opportunity for discovery of biomarkers that may 
predict response to therapy. 
TOTAL  
NUMBER OF 
SUBJECTS 
N = 20 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated ___18____ months after lead institution opens to 
accrual 
ESTIMATED STUDY 
DURATION  
Estimated 24 months  
 
 
 


 
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TABLE OF CONTENTS 
 
Schema ............................................................................................................................. 12 
1. 
Background and Rationale ................................................................................... 13 
2. 
Study Objectives and Endpoints........................................................................... 26 
3. 
Eligibility Criteria .................................................................................................. 27 
4. 
Subject Registration............................................................................................... 31 
5. 
Treatment Plan....................................................................................................... 31 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 35 
7. 
Study Calendar & Evaluations ............................................................................. 40 
8. 
Biospecimen Studies and Procedures ................................................................... 44 
9. 
Criteria for Disease Evaluation ............................................................................ 45 
10 
Drug Information ................................................................................................... 48 
11 
Adverse Events ....................................................................................................... 51 
12 
Statistical Methods ................................................................................................. 58 
13 
Trial Management ................................................................................................. 60 
14. Data Handling and Record Keeping .................................................................... 62 
15 
Ethics ....................................................................................................................... 63 
16 
References ............................................................................................................... 64 
17 
Appendices ............................................................... Error! Bookmark not defined. 
 
 
 
 
 


 
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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation 
or 
special term 
Explanation 
AChE 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion of patients alive and progression free at 12 months from 
randomization 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-28day 
Area under the plasma drug concentration-time curve from time zero to Day 
28 post-dose 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
 
 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cis 
Cycle 
Cisplatin 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
CCA 
Maximum plasma concentration at steady state 
Cholangiocarcinoma 
CR 
CRF 
Complete response 
Case Report Form 
CSA 
Clinical study agreement 
CSR 
Clinical study report 


 
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Abbreviation 
or 
special term 
Explanation 
CT 
CTNMO 
Computed tomography 
Clinical Trials Network and Monitoring Office 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
Ctrough,ss 
Trough concentration at steady state 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Durva 
Duration of response 
Durvalumab 
EC 
Ethics Committee, synonymous to Institutional Review Board and 
Independent Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Gem 
Good Clinical Practice 
Gemcitabine 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
ICC 
Investigator’s Brochure 
Intrahepatic Cholangiocarcinoma 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 


 
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Abbreviation 
or 
special term 
Explanation 
IFN 
Interferon 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product  
imAE 
Immune-mediated adverse event 
IRB 
Institutional Review Board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 


 
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Abbreviation 
or 
special term 
Explanation 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
sPD-L1 
Soluble programmed cell death ligand 1 
T3 
Triiodothyronine 
T4 
Thyroxine 


 
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Abbreviation 
or 
special term 
Explanation 
TSH 
Trem 
Thyroid-stimulating hormone 
Tremelimumab 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web-Based Data Capture 
WHO 
World Health Organization 
 
 


 
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SCHEMA 
 
 
 
 
 
 


 
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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
A neoadjuvant therapeutic approach is accepted for malignancies with a high rate of recurrence 
and poor overall survival. This is established practice in resectable, and borderline resectable 
pancreatic cancer. It is increasingly embraced for resectable hilar cholangiocarcinoma (CCA) prior 
to liver transplant. Given the aggressive nature of intrahepatic cholangiocarcinoma (ICC) - a high 
rate of recurrence/metastases accompanied by poor overall survival- neoadjuvant therapy is 
justified. As such, many experts recommend perioperative therapy for ‘borderline resectable’ 
intrahepatic cholangiocarcinoma (ICC). Borderline ICC is characterized by features that may 
hamper complete resection with negative margins (R0 resection). Some of these features also 
portend a significantly increased risk of local and distant recurrence. Based on data from the 
ABC02 trial for locally advanced and metastatic CCA, the combination of gemcitabine and 
cisplatin (GemCis) is the most widely used perioperative regimen for borderline resectable ICC. 
The objective response rate of 20% with this regimen in ICC argues for the development of more 
potent systemic therapy combinations, including chemotherapy and immunotherapy. Patients with 
borderline resectable ICC represent a population that would benefit from these more potent 
combination regimens. At the same time, drug development in this setting provides the opportunity 
to explore biomarkers that may predict response to therapy. 
 
1.1.1 Neoadjuvant therapy in intrahepatic cholangiocarcinoma 
Intrahepatic cholangiocarcinoma (ICC) carries a grim prognosis. Most patients (50-60%) present 
with locally advanced, metastatic, and therefore incurable disease. About 20-30% of patients have 
resectable disease, and a further 20% present with tumors that are ‘borderline resectable’. 
Tumors in the latter category are accompanied by high-risk features; large tumor size, 
multifocality, vascular invasion and regional lymph node involvement that suggest 
aggressive tumor biology. These features may render complete R0 challenging. This is 
important as achieving R0 resection provides the best opportunity for long term survival [1-
5]. Following curative intent surgical resection, up to 60% of patients will recur with local and 
distant disease. Five-year overall survival therefore remains low at about 30%, and long-term cure 
rate is estimated to be only 10%.[6] 
 
This state of affairs is similar to what obtains in pancreatic ductal adenocarcinoma (PDAC). Here, 
the therapeutic strategy has been based on development of more potent combination chemotherapy 
regimens in the metastatic setting (eg FOLFIRINOX) which have then been moved to the adjuvant 
and neoadjuvant settings [7-9]. Given the clinical similarities between the two entities, a similar 
approach may be required in ICC. However, drug development is hampered by the rarity of the 
disease. The role of neoadjuvant therapy in ‘borderline resectable’ ICC is thus still evolving. Many 
experts (within a multi-disciplinary tumor board setting) recommend systemic chemotherapy, 
usually gemcitabine and cisplatin to ‘test the biology’ of the disease and shrink the tumor, a la 
PDAC to increase the chances of R0 resection [10]. Neoadjuvant therapy is also employed in the 
relatively more common resectable and locally advanced perihilar and hilar cholangiocarcinoma. 
For example, in a retrospective study of 57 patients with perihilar CCA, neoadjuvant 
chemoradiotherapy (N=12) was associated with a median disease-free survival (DFS) of 26 
months compared 15.1 months in patients who did not receive neoadjuvant therapy (N=45)[11]. 
Neoadjuvant therapy is also employed prior to transplant in patients with resectable hilar 


 
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cholangiocarcinoma [12]. Importantly, patients with locally advanced ICC who receive 
neoadjuvant chemotherapy with regimens that are potentially inferior to GemCis (including 
gemcitabine and oxaliplatin)[13] achieve similar survival outcomes as those who have resectable 
disease[14]. 
 
The potency of the systemic treatment regimen is critical to the success of neoadjuvant therapy. 
The combination of gemcitabine and cisplatin (GemCis) is the only licensed regimen for metastatic 
cholangiocarcinoma, and capecitabine is recommended in the adjuvant setting [15, 16]. Based on 
this, GemCis is usually deployed in the neoadjuvant setting for ‘borderline resectable’ ICC. A 
single arm Phase II study is addressing the role of GemCis combined with nab-paclitaxel in 
high risk or borderline resectable ICC (NCT03579771). In addition, based on recent promising 
Phase II data in the locally advanced and metastatic settings[17], this regimen is being tested in a 
large randomized phase III trial (NCT03768414). However, in keeping with recent trends in 
oncology drug development, several trials are exploring the role of immunotherapy in combination 
with GemCis in metastatic ICC. This approach is justified given the recognized role of the immune 
system and tumor immune evasion mechanisms in determining outcomes in ICC [18].  
 
1.1.2 The immune system in Intrahepatic Cholangiocarcinoma 
Biliary tree cancers (BTC) are associated with chronic inflammation. The predominant 
inflammatory cells in BTC are T lymphocytes, and multiple studies have shown a prognostic role 
for tumor infiltrating cytotoxic lymphocytes (TIL) in cholangiocarcinoma [18]. One study reported 
CD8+ immunostaining in about 40% of CCA samples (N=16). The presence of CD8+ memory T 
cell infiltrates (12%) was associated with improved overall survival (HR 0.27, 95% CI 0.09-0.83, 
P=0.023)[19]. In addition, a systematic review and meta-analysis of 12 studies also suggested an 
association between improved clinical outcomes and higher expression of TILs. Despite this, in 
most patients with ICC, the tumor microenvironment is more immunosuppressive than pro-
inflammatory [20]. Nearly 50% of patient samples express PDL1 (=/> 1%), although the numbers 
vary depending on the cut off employed, and whether tumor cells, inflammatory cells or both are 
assessed [21, 22]. PDL1 expression is induced in tumors (and some immune cells) as a negative 
regulator of cytotoxic effector T cells[23]. Accordingly, in an investigation of the ‘genomic 
spectra’ of cholangiocarcinoma, up to 40% of samples were grouped into a cluster characterized 
by increased expression of immune related genes, cytokines and immune checkpoints including 
PDL1 [24]. This cohort (Cluster 4 of 4) was associated with the poorest prognosis, suggesting the 
success of tumor immune suppressive and evasive maneuvers.  
 
1.2 
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[25]  
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells [26].  It has 
2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273)[27].  The PD-1 and 
PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors, 
which can halt or limit the development of T cell response.  When PD-L1 binds to PD-1, an 
inhibitory signal is transmitted into the T cell, which reduces cytokine production and suppresses 
T-cell proliferation.  Tumor cells exploit this immune checkpoint pathway as a mechanism to 
evade detection and inhibit immune response. 


 
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PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages [28].  Importantly, 
PD-L1 is commonly over-expressed on tumor cells or on non-transformed cells in the tumor 
microenvironment [29].  PD-L1 expressed on the tumor cells binds to PD-1 receptor on the 
activated T-cells leading to the inhibition of cytotoxic T cells.  These deactivated T cells remain 
inhibited in the tumor microenvironment.  The PD-1/PD-L1 pathway represents an adaptive 
immune resistance mechanism that is exerted by tumor cells in response to endogenous anti-tumor 
activity. 
 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on immune 
cells. This activity overcomes PD-L1–mediated inhibition of antitumor immunity. While 
functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different 
from direct agonism of a stimulatory receptor such as CD28. 
 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the PD-
L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, 
supporting the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance 
antitumor immune response in cancer patients [30-35] with responses that tend to be more 
pronounced in patients with tumors that express PD-L1. In addition, high mutational burden e.g., 
in bladder carcinoma [36] may contribute to the responses seen with immune therapy. 
 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed by 
regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a negative regulatory 
signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on antigen-presenting 
cells[37]. (Fife and Bluestone, 2008) Blockade of CTLA-4 binding to CD80/86 by anti-CTLA-4 
antibodies results in markedly enhanced T-cell activation and antitumor activity in animal models, 
including killing of established murine solid tumors and induction of protective antitumor 
immunity. Therefore, it is expected that treatment with an anti-CTLA-4 antibody will lead to 
increased activation of the human immune system, increasing antitumor activity in patients with 
solid tumors. 
 
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and 
programmed death ligand 1 (PD-L1) has promising clinical activity. Ipilimumab was granted 
United States (US) Food and Drug Administration (FDA) approval for the treatment of metastatic 
melanoma and is currently under investigation for several other malignancies whilst nivolumab 
and pembrolizumab, two anti-PD-1 agents and atezolizumab, an anti PD-L1 agent have been 
granted approvals by agencies such as the United States of America Food and Drug Administration 
and the European Medicines Agency approval for the treatment of a number of malignancies 
including metastatic melanoma, squamous and non-squamous cell non-small-cell lung cancer and 
urothelial carcinoma. In addition, data from agents in the anti-PD-1/PD-L1class shows clinical 
activity in a wide range of tumor types. 


 
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1.2.1 Durvalumab 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 
on T cells and CD80 (B7.1) on immune cells (IC). It is being developed by AstraZeneca for use in 
the treatment of cancer. The proposed mechanism of action (MOA) for durvalumab is interference 
in the interaction of PD-L1 with PD-1 and CD80 (B7.1).  Blockade of PD-L1/PD-1 and PD-
L1/CD80 interactions releases the inhibition of immune responses, including those that may result 
in tumor elimination.  In vitro studies demonstrate that durvalumab antagonizes the inhibitory 
effect of PD-L1 on primary human T cells resulting in the restored proliferation of IFN-γ [38].  In 
vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a 
T-cell-dependent mechanism [38].  Based on these data, durvalumab is expected to stimulate the 
patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an 
antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity.  
 
To date durvalumab has been given to more than 8000 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized in Section 1.4.1.2. Refer to the current durvalumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information including 
safety, efficacy and pharmacokinetics.  
 
1.2.2 Tremelimumab  
Tremelimumab is a human immunoglobulin (Ig)G2 mAb that is directed against CTLA-4; cluster 
of differentiation (CD152), a cell surface receptor that is expressed primarily on activated T cells 
and acts to inhibit their activation. Tremelimumab completely blocks the interaction of human 
CTLA-4 with CD80 and CD86, resulting in increased release of cytokines (interleukin [IL]-2 and 
interferon [IFN]-γ) from human T cells, peripheral blood mononuclear cells and whole blood[39]. 
Tremelimumab is being developed by AstraZeneca for use in the treatment of cancer.  
 
To date tremelimumab has been given to more than 1500 patients as part of ongoing studies either 
as monotherapy or in combination with other anticancer agents. Details on the safety profile of 
tremelimumab monotherapy are summarized in Section 1.4.1.3. Refer to the current tremelimumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information including 
safety, efficacy and pharmacokinetics. 
 
1.2.3 Durvalumab with tremelimumab and platinum-based chemotherapy  
Because inhibition of CTLA4 and PD1/PDL1 activates the cytotoxic T-cells in a non-redundant 
fashion, the combination of antibodies against these 2 pathways provide at least an additive effect 
[40]. In melanoma, and RCC, the combination of an anti-PD1 agent (nivolumab) and ipilimumab 
(anti-CTLA4) is associated with significant survival benefit compared to either agent alone or with 
the standard of care treatment [41, 42]. This combination is being assessed in multiple Phase III 
studies for malignancies including NSCLC and hepatocellular cancer. In cancers, like NSCLC and 
small cell lung cancer (SCLC) ongoing studies are defining the role of combination 
immunotherapy with chemotherapy.  
 


 
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In addition to cytotoxicity that may potentially lead to an increase in the neoantigen load (albeit 
weakly), other mechanisms have been proposed to support an immunomodulatory role for 
traditional chemotherapy agents, including cisplatin [43, 44]. Based on preclinical models, 
cisplatin has been demonstrated to upregulate MHC class I antigen expression, fostering antigen 
presentation [45, 46]. In addition, cisplatin may down regulate an immunosuppressive 
microenvironment by reducing tumor myeloid suppressor cell and T reg infiltration and augment 
effector T cell recruitment and activity [47-49]. In the clinical setting, the combination of 
pembrolizumab with platinum-based chemotherapy is associated with a superior overall survival 
compared to chemotherapy alone in NSCLC [50] .  Based on these, several trials are ongoing to 
evaluate the activity and efficacy of the combination of single or doublet immunotherapy with 
platinum-based therapy. The NILE trial is an ongoing randomized Phase III trial of durvalumab 
+/- tremelimumab with platinum-based chemotherapy in locally advanced/metastatic bladder 
cancer (NCT03682068). A similar trial (CASPIAN) is active in extensive stage small cell lung 
cancer (NCT03043872) 
 
In cholangiocarcinoma, a phase III trial (Keynote 966) of GemCis and Pembrolizumab compared 
to GemCis alone is currently enrolling patients with locally advanced and metastatic 
cholangiocarcinoma (NCT04003636). A combination therapy of doublet immunotherapy (for 
instance, durvalumab and tremelimumab) with GemCis will be a natural progression of that study.  
 
1.3 
Research hypothesis 
This is a window of opportunity pilot trial to assess the activity, safety and feasibility of doublet 
immunotherapy and platinum-based chemotherapy in resectable intrahepatic cholangiocarcinoma 
with high risk features. The hypothesis is that the combination of durvalumab/MEDI4736 and 
tremelimumab (doublet immunotherapy) with platinum-based chemotherapy (gemcitabine and 
cisplatin) will yield an objective of 52% and improve complete resection rates in intrahepatic 
cholangiocarcinoma. This will facilitate margin negative resection and ultimately reduce 
recurrence rates and improve survival. Carrying out this trial in the neoadjuvant setting potentially 
allows improved overall survival and also provides an opportunity for discovery of biomarkers 
that may predict response to therapy. 
 
1.4 
Rationale for conducting this study 
The purpose of the study is to assess the activity of doublet immunotherapy and platinum-based 
chemotherapy in resectable intrahepatic cholangiocarcinoma with high features. As noted in the 
background (Section 1.1), long term survival remains poor even in resectable intrahepatic 
cholangiocarcinoma as majority of patients recur. Patients with high risk features are more likely 
to have disease recurrence following curative intent resection. A neoadjuvant approach with 
systemic therapy improves margin negative resection (R0 resection with margins negative for 
microscopic tumor involvement) and this is an important prognostic determinant in ICC. A 
neoadjuvant approach may also treat micro-metastatic disease although this has not been proven 
in intrahepatic cholangiocarcinoma. Achieving significant shrinkage is therefore vital. The current 
standard therapy regimen used in this setting is the combination of gemcitabine and cisplatin which 
is associated with an ORR of 20-25%[15]. This study proposes to improve ORR from 25% to 52%. 
If the objectives are achieved, this will serve as justification to expand the use of this combination 
to a larger cohort of patients with locally advanced and metastatic biliary tree cancer. 
 


 
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Because this is a pilot study, and given the rarity of the disease entity, there will be no control 
group. All patients enrolled will receive the study intervention. There will be no blinding of 
investigators or patients. Patients will receive up to 4 cycles of interventional agents prior to 
surgical resection. Patients will receive imaging scans after the 2nd and 4th cycle (before surgery) 
of intervention agents. The primary endpoint of the study is objective response rate (ORR). The 
objective response rate is an easy to measure, early indicator of activity of intervention agents. 
Although it is clear that ORR is not a reliable predictor of overall survival, in the neoadjuvant 
setting, where the goal is to ‘shrink’ the tumor, an improvement in response rate is a useful 
surrogate for clinical benefit[51]. The short interval of scans (6 weeks) allows investigators to 
identify non responders. These patients may be encouraged to come off study and be treated based 
on the treating oncologist’s choice. Since the investigational agents include ‘standard of care’ 
agents, a good argument can be made that these patients would not have benefitted from standard 
therapy only. Patients with at least stable disease after the 2nd treatment cycle will proceed with 
study interventions. However, patients with radiologic progression but who remain clinically 
stable may be allowed to continue treatment if the patient elects to, pending confirmation of 
progression and after a discussion between the investigator and sponsor-investigator. 
 
An important secondary endpoint is safety of the study interventions. We have defined a dose 
limiting toxicity probability level of 20% with early stopping rules based on this. The time to 
accrual of patients will also provide insight into the feasibility and design of larger trials that may 
focus on resectable ICC with high risk features. Justifications for the different dosing and schedule 
of treatment are noted in the protocol below.  
 
1.4.1 Gemcitabine + cisplatin combination therapy dose rationale 
The dose of chemotherapy (gemcitabine and cisplatin) chosen for this trial is the standard approved 
dose and schedule based on the ABC02 trial. Medical oncologists use this regimen in patients with 
resectable ICC and high-risk features setting as described in this protocol (Inclusion criteria, 
Section 4.1). Multiple clinical trials aimed at improving the combination have added newer 
therapies to this backbone regimen. 
 
1.4.2 Durvalumab + tremelimumab combination therapy dose rationale 
The durvalumab + tremelimumab doses and regimen selected for this study are based on the goal 
of selecting a combination dose of durvalumab and tremelimumab that would yield sustained target 
suppression (sPD-L1), demonstrate promising efficacy and have an acceptable safety profile.  
 
1.4.2.1 
Pharmacokinetics/Pharmacodynamics data  
Study D4190C00006 included dose cohorts with both a Q4W and a Q2W schedule of durvalumab 
in combination with a Q4W schedule of tremelimumab. The Q4W schedule was included to align 
with the Q4W dosing of tremelimumab. PK simulations from durvalumab monotherapy data 
indicated that a similar area under the plasma drug concentration-time curve at steady state (AUCss; 
4 weeks) was expected following both 10 mg/kg Q2W and 20 mg/kg Q4W dosing with 
durvalumab. The observed durvalumab PK data from the D4190C00006 study were in line with 
the predicted monotherapy PK data developed pre-clinically and in line with that seen in the first-
time-in-human (FTIH), single agent study (CD-ON-MEDI4736-1108) in patients with advanced 
solid tumors. This demonstrates similar exposure of durvalumab 20 mg/kg Q4W and 10 mg/kg 
Q2W, with no alterations in PK when durvalumab and tremelimumab (doses ranging from 1 to 3 


 
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mg/kg) are dosed together. While the median maximum plasma concentration 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.  
 
1.4.2.2 
Clinical data  
In Study D4190C00006 various dose combinations have been explored, with doses of 
tremelimumab ranging from 1 to 10 mg/kg and doses of durvalumab ranging from 3 to 20 mg/kg. 
Tremelimumab was given on a Q4W schedule whilst durvalumab was explored in both a Q4W 
and Q2W schedule, with the goal of identifying the dose combination that best optimizes the 
benefit-risk profile in an acceptable range of PK and pharmacodynamic values. 
 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 
10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the q2w schedule, the number of patients reporting any AE, Grade 
3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar 
pattern was noted in the q4w regimens, suggesting that, as the dose of tremelimumab increased 
above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, the SAEs 
frequently attributed to immunotherapy, pneumonitis 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 when combined with durvalumab. As a result, all combination 
doses utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final dose 
selection.  
 
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab 
may not impact the safety of the combination as much as the tremelimumab dose. Further, safety 
data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in safety events 
with increasing dose of durvalumab.  
 
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had a tolerable safety profile, but still showed strong 
evidence of clinical activity. No dose-limiting toxicities (DLTs) were reported in this cohort.  
 
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15- and 20-mg/kg durvalumab q4w cohorts 


 
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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. Of the 14 patients in this 
cohort, there were 4 patients (29%) with PR, 4 patients (29%) with SD, and 2 patients (14%) with 
PD. Two patients were not evaluable for response. 
 
Altogether, the data suggested that a 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose 
combination should be selected for further development. To date more than 3000 patients have 
received the combination using a number of doses and dosing schedules. Details on the safety 
profile of durvalumab + tremelimumab combination therapy are summarized in Sections 1.4.2. 
Refer to the current editions of the durvalumab and tremelimumab IBs for a complete summary of 
non-clinical and clinical information including safety, PK and efficacy. 
 
Refer to the current durvalumab Investigator’s Brochure for a complete summary of non-clinical 
and clinical information on the durvalumab + tremelimumab combination, including safety, 
efficacy and pharmacokinetics.  
 
1.4.3 Rationale for 4 cycles of combination therapy before surgical resection 
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[52].  
 
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W.  (For 
further information on PK observations in Study 006, please see the current IB).   
 
Registered clinical trials of neoadjuvant therapy for cholangiocarcinoma have administered 3-6 
cycles of systemic therapy over 9 to 12 weeks (NCT02256982, NCT03603834, NCT03579771). 
With this approach patients receive optimal systemic therapy to facilitate tumor shrinkage without 
unduly delaying surgery. In addition, this time period is sufficient to test the biology of the disease, 
as patients whose tumors progress in this time period on systemic therapy have aggressive disease, 
and surgical extirpation would not have improved their overall outcome.  
 
The combination regimen will be administered for 4 doses Q3W unless other specific 
discontinuation criteria are met.  
 
1.4.4 Rationale for fixed dosing of durvalumab and tremelimumab 
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
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 the PK of 
durvalumab (coefficient of ≤0.5). The impact of body WT-based (10 mg/kg Q2W or 20 mg/kg 


 
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Q4W) and fixed dosing (750 mg Q2W or 1500 mg Q4W) of durvalumab was evaluated by 
comparing predicted steady state PK exposures (AUCss,0-28, Cmax,ss, and Cmin,ss) using the 
population PK model. A fixed dose of 750 mg Q2Wwas selected to approximate 10 mg/kg Q2W 
and a fixed dose of 1500 mg Q4W was selected to approximate 20 mg/kg Q4W (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 (10 mg/kg Q2W) and fixed dosing 
(750 mg Q2W) regimens yield similar median steady state Q2W and a fixed dose of 1500 mg 
Q4W was selected to approximate 20 mg/kg Q4W. 
 
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)[53]. 
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 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 kg 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-patient variability with fixed dosing regimen. 
Similar findings have been reported by others [54-57]. 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-patient variability in pharmacokinetic/pharmacodynamics parameters.  
 
These fixed dose regimens are being investigated in early and late phase trials (NCT02527434, 
NCT03084471) and are already in use in the community. 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 
 
The feasibility and safety of a 3-week dosing regimen of platinum chemotherapy and durvalumab 
+ tremelimumab was explored in a phase 1b study carried out in South Korea and Japan 
(NCT02658214). Here, 32 patients with advanced solid tumors received 1120mg (equivalent to 
the 1500mg q4week dose) of durvalumab and 75mg (minimum available biologic effective dose) 
of tremelimumab in addition to 1st line chemotherapy. Also, data from the Canadian Clinical Trials 
Group provide early safety data for the combination of platinum doublet chemotherapy with 
doublet immunotherapy (NCT02537418). In addition, PK modelling suggests that 3-weekly 
dosing would result in slightly higher Cmax and Cmin but a lower Area under the Curve (AUC) 
compared to a 4-weekly regimen (AstraZeneca data).  This suggests that a 3 weekly schedule 
would preserve activity without significantly impacting safety risks Based on this, the NILE study 
is an ongoing Phase III trial assessing the efficacy of 3- weekly cisplatin/carboplatin + gemcitabine 
in combination with durvalumab (1120mg) +/-tremelimumab (75mg) in locally advanced and 
metastatic bladder cancer. In our study, patients will receive 4 cycles of gemcitabine and cisplatin 
per standard of care on day 1 and day 8 in addition to a fixed dose of durvalumab 1500mg 
(supported by PK modeling data) on day 1 every 3 weeks for 4 cycles.   
 


 
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However, in the present study, 300mg of tremelimumab will be administered only once on 
Cycle 1 day 1. This is equivalent to 75mg of tremelimumab delivered every cycle for 4 cycles.  
 
This is based on simulation data which suggests that the Cmax obtained after a single dose 
administration of tremelimumab at 4mg/kg is 4 times higher than the predicted Cmax after the 4th 
cumulative dose of tremelimumab administered at 1mg/kg every 4 weeks regimen (78ug/ml vs 
19ug/ml). This single administration of higher dose of tremelimumab may deliver better antitumor 
activity and reduce cumulative toxicity associated with repeated dosing. The safety of this 
immunotherapy dosing combination is currently being assessed in the ongoing Phase I/II 
HIMALAYA study in patients with hepatocellular cancer (NCT03298451). No new safety signals 
have been reported so far. Our study will add on to this by assessing the safety of the combination 
with platinum-based therapy.  
 
1.5 
Benefit-risk and ethical assessment 
 
1.5.1 Potential benefits 
The combination of chemotherapy with single agent immune checkpoint inhibitor therapy (anti 
PD1/PDL1) has consistently been associated with an improvement in ORR in the first line 
treatment of metastatic disease across multiple tumors. In NSCLC, this combination is associated 
with an ORR of about 50% compared to 20% with chemotherapy only[50, 58]. In addition, in the 
Phase III KEYNOTE-062 trial, involving patients with HER2-ve metastatic gastric cancer, the 
combination of chemotherapy and pembrolizumab (anti-PD1) was also associated with superior 
ORR compared to SoC chemotherapy only [59]. 
 
Similar results have been established in cholangiocarcinoma. Ueno and colleagues reported an 
ORR of 36.7% among 30 patients with locally advanced/ metastatic cholangiocarcinoma who 
received treatment in the first line setting with GemCis and nivolumab [60]. This was a single arm 
study. It is noteworthy, however, that historically, an ORR of about 20% is expected with SoC 
chemotherapy in cholangiocarcinoma. The median OS in this cohort was 15.4 months (90% CI 
11.8 to not estimable) at the time of reporting.  Interestingly, the combination of ipilimumab and 
nivolumab offered in the 3rd line setting and beyond in another phase I study yielded a median OS 
of 10 months[61]. This is similar to the OS reported in the ABC02 trial with SoC chemotherapy 
administered in the first line. It is expected that the combination of doublet immunotherapy with 
GemCis will achieve a higher ORR than GemCis combined with an anti-PD1 agent alone.  
 
While an ORR may not be an optimal surrogate for overall survival in the advanced and metastatic 
cancer setting [62], it may provide the opportunity to improve margin negative resection in the 
neoadjuvant setting. An ORR is therefore a useful metric in the neoadjuvant setting, and the 
combination of doublet immunotherapy with chemotherapy may potentially double the number of 
patients who become eligible for margin negative resection. Furthermore, a pathologic complete 
response, which is more likely with more potent systemic therapy may also be a marker for 
prolonged survival or cure. 
 
There are risks inherent to neoadjuvant therapy trials. Tumors may progress in the time before 
surgical intervention. Given our current understanding of the biology of cancer, tumor progression 
while on standard therapy suggests aggressive disease. In a way, patients who fall into this category 
may have been spared surgical resection with the potential complications that may accompany it. 


 
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Surgery in this case may not have been helpful to the patient. Secondly, the use of systemic 
chemotherapy, and particularly in combination with immunotherapy may lead to adverse effects 
that may preclude eventual surgical resection. Safety guidelines are in place in this protocol to 
reduce the number of patients who may be impacted by this. In addition, exclusion criteria for this 
protocol have been designed to exclude patients who may be affected by this. We recognize that 
this is a risk that cannot be completely eliminated.  
 
In summary, this study offers patients the opportunity of an increased likelihood of a margin 
negative resection which overall, increases the chance of long-term survival and potential for cure 
in this setting of high-risk disease. 
 
1.5.1.1 Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the potential for 
adverse effects on other tissues. 
 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are thought 
to be due to the effects of inflammatory cells on specific tissues. These risks are generally events 
with a potential inflammatory or immune mediated mechanism, and which may require more 
frequent monitoring and/or unique interventions such as immunosuppressant and/or endocrine 
therapy. These immune mediated effects can occur in nearly any organ system and are most 
commonly seen as gastrointestinal AEs such as colitis and diarrhea, pneumonitis/interstitial lung 
disease (ILD), hepatic AEs such as hepatitis and liver enzyme elevations, skin events such as rash 
and dermatitis and endocrinopathies including hypo- and hyper-thyroidism. 
 
1.5.1.2 Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, hypophysitis and adrenal 
insufficiency) 
hepatitis/increases 
in 
transaminases, 
nephritis/increases 
in 
creatinine, 
pancreatitis/increases 
in 
amylase 
and 
lipase, 
rash/pruritus/dermatitis, 
myocarditis, 
myositis/polymyositis, other rare or less frequent inflammatory events including neurotoxicity, 
infusion-related reactions, hypersensitivity reactions and infections/serious infections.  
 
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab IB. 
 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 15% of patients) are 
fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, 
pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9.4% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 6.5% of patients experienced an SAE that was considered to be 
related to durvalumab by the study investigator. 
 


 
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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 (please see Appendix 1). 
 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB. 
 
1.5.1.3 Tremelimumab 
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, diarrhea, 
enterocolitis and intestinal perforation), endocrine disorders (hypo and hyperthyroidism, 
hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), elevations in lipase and 
amylase and clinical manifestations of pancreatitis, other gastrointestinal events e.g. ulcerative 
colitis, dehydration, nausea and vomiting; hepatic events including hepatitis, and liver enzyme 
elevations; pneumonitis and ILD; nervous system events including encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barre and proximal muscle weakness; cytopenia including 
thrombocytopenia, anemia and neutropenia; infusion-related reactions, anaphylaxis, and allergic 
reactions; renal events including renal failure, acute kidney injury, nephritis, nephrotic syndrome, 
autoimmune nephritis and electrolyte abnormalities such as hypokalemia; autoimmune diseases 
including autoimmune arthritis, Sjogren's syndrome and giant cell temporal arteritis; 
hyperglycemia and diabetes mellitus; and pyrexia.  
 
For information on all identified and potential risks with tremelimumab please always refer to the 
current version of the tremelimumab IB. 
 
Using pooled data from monotherapy clinical studies AEs (all grades) reported very commonly (≥ 
10% of patients) were diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, vomiting, 
dyspnea, constipation, cough, pyrexia, abdominal pain, decreased weight, headache, asthenia, and 
anemia. Approximately 16% of patients experienced an AE that resulted in permanent 
discontinuation of tremelimumab and approximately 45% of patients experienced an SAE. 
A detailed summary of tremelimumab monotherapy AE data can be found in the current version 
of the tremelimumab IB. 
IB. 
 
1.5.2 Durvalumab + tremelimumab  
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study 006, in patients with NSCLC, and is being 
studied in a number of other ongoing clinical trials, in a number of different indications, and has 
to date shown a manageable safety and tolerability profile.   
The types of risks with the combination of durvalumab + tremelimumab (based on an equivalent 
durvalumab dose of 20m/kg and a tremelimumab dose of 1mg/kg) are similar to those for 
durvalumab and tremelimumab monotherapy. Emerging data from study 006, other studies 
evaluating the combination, and from combinations of other agents in the same class indicate an 
increased frequency and/or severity of some of these immune-mediated toxicities. 
 
For information on all identified and potential risks with the durvalumab + tremelimumab 
combination please always refer to the current version of the durvalumab IB. 


 
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In durvalumab + tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥ 10% of patients) are fatigue, 
diarrhea, nausea, dyspnea, decreased appetite, pruritus, vomiting, anemia, constipation, cough, 
abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism, asthenia, edema peripheral, 
decreased weight, decreased hyponatremia and rash.  
 
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation of 
study drug and approximately 16% of patients experienced an SAE that was considered to be 
related to durvalumab and tremelimumab by the study investigator. 
 
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB. 
 
1.5.3 Durvalumab + tremelimumab + gemcitabine + cisplatin 
Preliminary data from the Canadian Clinical Trial Group (CCTG) Phase I study (NCT02537418), 
of single (durvalumab) or doublet immunotherapy (durvalumab and tremelimumab) in 
combination with platinum-based chemotherapy (including GemCis) in advanced and metastatic 
solid tumors suggests that the combination is tolerable with manageable side effects. Of the 118 
patients who have received up 723 cycles of therapy, immune related adverse events (irAEs) were 
reported in 50% of patients. Grade 3 or higher irAE was documented in in 10%, mainly involving 
the skin and the gastrointestinal tract. Although biochemical abnormalities occurred in 74% of 
patients on chemotherapy and doublet immunotherapy, these were generally manageable. 
Importantly, only 15 patients (12%) discontinued therapy due to Grade 2 or higher irAEs. There 
were no grade 5 events reported [63]. 
 
1.5.4 Overall benefit-risk 
Given the manageable toxicity profile of the platinum-based chemotherapy and doublet 
immunotherapy combinations, a phase III trial of GemCis and immunotherapy doublet 
(durvalumab and tremelimumab) is ongoing in the 1st line for locally advanced and metastatic 
bladder cancer (NCT03682068). Interestingly, the dose of cisplatin administered per cycle is 
higher (70mg/m2 on day 1 every 3 weeks) in bladder cancer compared to CCA (25mg/m2 on 
days 1 and 8 every 3 weeks). There have been no new safety signals reported with this 
combination (discussions with UAB principal investigator and AstraZeneca representatives) and 
adverse effects have been manageable.  In addition, given the low ORR achieved with SOC 
treatment with gemcitabine and cisplatin, exploring a potentially more potent therapy combination 
is justified. This may improve surgical resection rates and provide improved long-term survival. 
Furthermore, because of the heterogenous nature of intrahepatic cholangiocarcinoma, 
administering systemic therapy in the neoadjuvant setting provides an opportunity to define patient 
and tumor specific characteristics that may determine response to therapy. 
 
 
 


 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Determine the objective response rate (ORR) of the combination of platinum-based chemotherapy 
(GemCis) combined with doublet immunotherapy (Durva/Trem) in borderline resectable 
intrahepatic cholangiocarcinoma 
 
2.1.2 Secondary Objectives 
• Assess the feasibility of neoadjuvant platinum-based chemotherapy (GemCis) and doublet 
immunotherapy for high-risk but technically resectable (borderline resectable) intrahepatic 
cholangiocarcinoma. 
• Determine the safety of the combination of platinum-based chemotherapy (GemCis) and 
doublet 
immunotherapy 
(Durva/Trem) 
in 
borderline 
resectable 
intrahepatic 
cholangiocarcinoma 
• Determine feasibility of enrolling patients into a large Phase II/III trial of ICC. 
 
2.1.3 Correlative/Exploratory Objectives 
Evaluate blood and tumor-based biomarkers that may be associated with improved ORR to 
combination of platinum-based chemotherapy (GemCis) and doublet immunotherapy 
(Durva/Trem) 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
Evaluate the objective response rate (ORR) a composite of complete and partial responses, with 
the combination of platinum based (GemCis) and doublet immunotherapy (Durva/Trem) after 2 
cycles of therapy and prior to surgical resection. 
 
2.2.2 Secondary Endpoints 
• Feasibility of administering this regimen will be assessed by 3 criteria 
o Determine the rate of completion of preoperative therapy (4 cycles). 
o Determine the rate of R0 resection with combination chemotherapy and doublet 
immunotherapy. 
o Determine pathologic complete response rate. (complete absence of foci invasive 
adenocarcinoma) 
• Assess adverse events via NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
v5 during therapy with stopping rules for dose limiting toxicity per Inova et al [64].  
• Determine the time to complete enrollment of patients, and the number enrolled over a 24-
month period. 
 
 
 


 
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3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Histologically/cytologically confirmed diagnosed intrahepatic cholangiocarcinoma 
 
2. Measurable disease based on RECIST 1.1 and have 1 or more radiologic features 
compatible with high risk (for resection and recurrence) but still considered technically 
resectable per multidisciplinary tumor board (Surgical oncologist, radiologist and medical 
oncologist minimum) meeting. High risk features would include at least 1 of the following 
criteria- 
• A large tumor (> 5cm) that would benefit from preoperative tumor shrinkage with 
systemic therapy 
• T1b-T4 tumor thought to be technically resectable 
• Multifocal tumors/ a tumor with satellite lesions confined to the same lobe, thought 
to be technically resectable 
• Suspicious or involved lymph nodes (N1) thought to be technically resectable 
• Tumor with any vascular involvement/invasion considered technically resectable 
• No extrahepatic metastases 
 
3. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
Written informed consent and any locally required authorization (e.g., Health Insurance 
Portability and Accountability Act in the US) obtained from the patient/legal representative 
prior to performing any protocol-related procedures, including screening evaluations.   
 
4. Adult male or female age >18 years at time of study entry  
 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  
 
6. Life expectancy of > 6 months 
 
7. Body weight >30 kg  
 
8. Adequate normal organ and marrow function as defined below:  
• Hemoglobin ≥ 10.0 g/dL 
• Absolute neutrophil count (ANC ≥1.5 x 109/L (> 1500 per mm3) 
• Platelet count ≥100 x 109/L (>75,000 per mm3) 
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not 
apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis 
or hepatic pathology), who will be allowed only in consultation with the sponsor. 
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal  


 
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• Measured creatinine clearance (CL) >60 mL/min or Calculated creatinine clearance 
CL>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 
24-hour urine collection for determination of creatinine clearance: 
 
9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female 
pre-menopausal patients. Women will be considered post-menopausal if they have been 
amenorrhoeic for 12 months without an alternative medical cause. The following age-
specific requirements apply:  
• Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
 
10.  Patient 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. 
 
11. Provide archival tumour tissue sample or newly obtained core or excisional biopsy of a 
previously unirradiated tumour lesion. Tissue blocks are preferred but unstained cut slides 
acceptable. In addition, should be open to undergoing a biopsy after at least 2 cycles of 
therapy. Patients who do not undergo surgical resection after 4 cycles will be advised to 
undergo another biopsy. 
 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
 
1. Has had previous local (surgery, radiation, embolizing procedure) or systemic therapy for 
borderline resectable intrahepatic cholangiocarcinoma. 
 
2. Participation in another clinical study with an investigational product during the last 3 
months. 
 
3. Concurrent enrolment in another clinical study, unless it is an observational (non-
interventional) clinical study or during the follow-up period of an interventional study. 
 
4. Has ampullary cancer, extrahepatic cholangiocarcinoma or gall bladder cancer. 
 
5. Patients with distant extrahepatic metastatic disease including distant (non-regional lymph 
nodes). NOTE: Regional lymph nodes depend on tumor site; for left sided lesions, regional 


 
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lymph nodes include inferior phrenic, hilar and gastrohepatic lymph nodes. For right sided 
lesions, regional lymph nodes include hilar periduodenal and peripancreatic lymph nodes. 
 
6. Has any other histologic subtype except adenocarcinoma or mixed histology with 
adenocarcinoma/hepatocellular carcinoma. 
 
7.  Any unresolved toxicity NCI CTCAE Grade > 2 from previous anticancer therapy except 
for alopecia, vitiligo and the laboratory values defined in the inclusion criteria. 
 
8. Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the sponsor-investigator. 
 
9. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment 
with durvalumab or tremelimumab may be included only after consultation with the 
sponsor-investigator. Any medical contraindication to the use of platinum-based doublet 
chemotherapy as judged by the treating physician. 
  
10. . Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of study drugs. 
 
11. History of allogenic organ transplantation. 
 
12. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: 
• Patients with vitiligo or alopecia 
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement  
• Any chronic skin condition that does not require systemic therapy 
• Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician 
• Patients with celiac disease controlled by diet alone 
 
13.  Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhoea, or psychiatric illness/social situations that would limit 
compliance with study requirement, substantially increase risk of incurring AEs or 
compromise the ability of the patient to give written informed consent. 
 
14. History of active primary immunodeficiency. 
 
 
 


 
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15. History of another primary malignancy except for 
• Malignancy treated with curative intent and with no known active disease ≥3 years 
before the first dose of IP 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 
 
16. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local practice), 
hepatitis B (known positive HBV surface antigen (HBsAg) result), Patients with a past or 
resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] 
and absence of HBsAg) are eligible. hepatitis C, Patients positive for hepatitis C (HCV) 
antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Testing 
for HIV is not required at screening but patients with known HIV disease will be excluded 
from the study. 
 
17. Current or prior use of immunosuppressive medication within 14 days before the first dose 
of durvalumab or tremelimumab. The following are exceptions to this criterion: 
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
 
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug. 
NOTE: Patients, if enrolled, should not receive live vaccine whilst receiving study drug 
and up to 30 days after the last dose of study drug. 
 
19. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from screening 
to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of 
durvalumab + tremelimumab combination therapy. 
 
20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
 
21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical 
study regardless of treatment arm assignment.   
 
22. Has had severe hypersensitivity (≥ Grade 3) to anti –PD1/PDL1 or anti-CTLA4 therapy 
and/or any of their excipients in the past.   
 
 
 


 
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23. Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4: 
• Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy. All AEs while receiving prior immunotherapy must have 
completely resolved or resolved to baseline prior to screening for this study. 
• Must not have experienced a ≥Grade 3 immune related AE or an immune related 
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: 
Patients with endocrine AE of ≤Grade 2 are permitted to enrol if they are stably 
maintained on appropriate replacement therapy and are asymptomatic. 
• Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, not have experienced recurrence of 
an AE if re-challenged, and not currently require maintenance doses of > 10 mg 
prednisone or equivalent per day. 
 
24. Judgment by the investigator that the patient is unsuitable to participate in the study and 
the patient is unlikely to comply with study procedures, restrictions and requirements.  
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through the UAB Clinical Trials Network and Monitoring Office’s 
(CTNMO). Subjects must be registered prior to starting protocol therapy. Patients will be identified 
following discussions at multidisciplinary tumor board meetings or following discussions among 
at least a medical oncologist, radiologist and surgical oncologist that patients confirmed 
intrahepatic cholangiocarcinoma is resectable but has high risk features as defined in this protocol. 
 
5. 
TREATMENT PLAN 
This is an open-label, window of opportunity, multicenter trial to determine the activity and safety 
of the combination of platinum-based chemotherapy (gemcitabine and cisplatin) with doublet 
immunotherapy (durvalumab and tremelimumab) as preoperative therapy in patients with 
histologically 
and 
radiologically 
documented 
borderline 
resectable 
intrahepatic 
cholangiocarcinoma.  
 
The study will plan to enroll 20 patients across 4 centers over a 2-year period. It is estimated that 
each center will enroll 2 patients per year. 
 
5.1 
Study Treatment Administration 
All patients will receive the same treatment and each cycle equals 21 days. For cycle 1, enrolled 
patients will receive 1 dose of tremelimumab 300 mg via IV infusion over 60 minutes, which will 
be followed by durvalumab 1500 mg via IV infusion over 60 minutes.  Cisplatin 25mg/m2 and 
gemcitabine 1000mg/m2 will be administered based on institutional guidelines and practice. 
 
For cycles 2 to 4, tremelimumab will not be given. Patients will receive durvalumab 1500mg over 
60 minutes followed by cisplatin 25mg/m2 and gemcitabine 1000mg/m2 administered as an IV 
infusion according to prescribing information or institutional standards.  
 
 


 
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Drug 
Dose1 
Route2 
Schedule3 
Cycle 
Length 
Total # of 
Cycles 
Tremelimumab 
300 mg 
Intravenously 
(IV) 
over 1 hour before 
durvalumab 
Day 1  
3 weeks  
(21 days) 
1 
Durvalumab 
1500 mg 
IV 1 hour after 
completion 
of 
tremelimumab 
Day 1  
4 
Gemcitabine 
1000 mg/m2 
IV per institutional 
standards  
Day 1, 8 
Cisplatin 
25 mg/m2 
Day 1, 8 
1 Dosing calculations should be based on actual body weight where applicable. Institutional standards for 
recalculating the dose based on weight changes should be used. All doses should be rounded up or to the nearest 
milligram per institutional standard.  
2 Tremelimumab will be administered first followed by durvalumab. Cisplatin + gemcitabine will then be 
administered. Infusion administration times performed outside the above recommended windows will not be 
considered as protocol deviations.  
3 A window of ± 3 days may be applied to all study visits to accommodate observed holidays, inclement weather, 
scheduling conflicts etc. Date and time of each drug administration should be clearly documented in subject’s 
chart and electronic case report forms (eCRFs). 
 
5.2 
Study Medications 
On the first infusion day, patients will be monitored, and vital signs collected/recorded in eCRF 
prior to, during and after infusion of study medications. Prior to the beginning of the infusions 
(measured once from approximately 30 minutes before up to 0 minutes [i.e., the beginning of the 
infusion]), approximately 30 minutes during the infusion (halfway through infusion) and at the 
end of the infusion (approximately 60 minutes ±5 minutes). If the infusion takes longer than 60 
minutes, then BP and pulse measurements should follow the principles as described above or be 
taken more frequently if clinically indicated.  
 
For subsequent infusions BP, pulse and other vital signs should be measured, collected/recorded 
in eCRF prior to the start of the infusion. Patients should be carefully monitored, and BP and other 
vital signs should be measured during and post infusion as per institution standard and as clinically 
indicated.  
 
A 60-minute observation period after each immunotherapy agent is administered is recommended 
at least for Cycle 1.  
 
5.2.1 Tremelimumab 
Tremelimumab will be administered over 1 hour (± 15 minutes). Tremelimumab will be 
administered first followed by durvalumab approximately 60 minutes (maximum 2 hours) after 
the end of the tremelimumab infusion.  If there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature per infusion. Institutional standards for patient 
monitoring during tremelimumab infusion should be utilized. Please refer to the current IB for 
more detailed information. 
 
 
 


 
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5.2.2 Durvalumab 
Durvalumab will be administered over 1 hour (± 15 minutes). If there are interruptions during 
infusion, the total allowed time should not exceed 8 hours at room temperature per infusion. If no 
issues are seen after durvalumab is given during the first cycle, the observation period after 
durvalumab administration may be reduced to 30 minutes. Institutional standards for patient 
monitoring during durvalumab infusion should be utilized. Please refer to the current IB for more 
detailed information. 
 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of durvalumab may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the initial 
rate until completion of the infusion. For patients with a ≤ Grade 2 infusion related reaction, 
subsequent infusions may be administered at 50% of the initial rate. Acetaminophen and/or an 
antihistamine (eg, diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator. If the infusion related reaction is ≥ Grade 3 or 
higher in severity, study drug will be discontinued. 
 
For management of patients who experience an infusion reaction, please refer to the toxicity and 
management guidelines in the Appendix 
 
NOTE: If a patient’s weight falls to 30 kg or below (≤ 30 kg), then the patient should receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab Q3W after consultation between the 
sponsor-investigator and site investigator, until the weight improves to above 30 kg (> 30 kg), at 
which point the patient should start receiving the fixed dosing of durvalumab 1500 mg. 
 
5.3 
Dose Limiting Toxicities 
Dose-limiting toxicities (DLTs) will be evaluated during the first 2 cycles of study treatment (over 
a 6-week period).  In other words, the period for evaluating DLTs will be from the time of first 
administration of tremelimumab Cycle 1 Day1 until Cycle 2 Day 21 (1 dose of tremelimumab and 
2 doses of durvalumab). Patients who do not remain on the study up to this time for reasons other 
than DLT may be replaced following consultation among the site investigator and sponsor-
investigator. Grading of DLTs will follow the guidelines provided in the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  
 
Since safety is a key secondary objective of this study, stopping boundaries, based on a Pocock 
style continuous reassessment method will be employed (see Section 12.7). Patients will be 
assessed on an ongoing fashion and if the numbers of dose limiting toxicities (DLT) reach the 
threshold based on those rules, a decision will be made to stop the study.  
 
A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to the 
investigational regimen (IR), with two exceptions: any grade of vitiligo or alopecia will not qualify 
as a DLT. AEs that are at least possibly related to durvalumab and/or tremelimumab-containing 
regimens shall be assessed as DLTs if they meet any of the following criteria: 
 
Hematologic toxicity: 
• Grade ≥ 3 neutropenia complicated by fever >38.3°C 
• Grade 4 neutropenia (lasting more than 7 days) 


 
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• Grade ≥ 3 thrombocytopenia with significant bleeding 
• Grade 4 thrombocytopenia (regardless of duration) 
• Grade 4 anemia (regardless of duration) 
 
Non-hematologic toxicity: 
• Any Grade 4 non-immune-mediated AE 
• Any Grade 4 immune-mediated AE, excluding endocrinopathies 
• Any Grade 3 non-immune mediated AE that does not resolve to Grade ≤ 1 or baseline 
within 28 days with optimal medical management 
• Any Grade 3 immune-mediated AE – excluding diarrhea/colitis, pneumonitis, hepatitis, 
rash, neurotoxicity, myocarditis, myositis/polymyositis, endocrinopathies and nephritis – 
that does not resolve to Grade ≤ 1 or baseline within 28 days after onset of the event despite 
optimal medical management including systemic corticosteroids 
• Grade 3 diarrhea or colitis that does not resolve to Grade ≤ 1 within 14 days [both immune- 
and non-immune-mediated indicated here; the same is the case if not specified in remaining 
bullet points below] 
• Grade 3 noninfectious pneumonitis 
• Grade 2 noninfectious pneumonitis that does not resolve to ≤Grade 1 within 3 days of the 
initiation of maximal supportive care 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN with 
concurrent increase in total bilirubin (TBL) ≥2×ULN without evidence of cholestasis or 
alternative explanations (e.g., viral hepatitis, disease progression in the liver; i.e., “Hy’s 
Law”) 
• ALT or AST >8×ULN or TBL>5×ULN 
• Grade 3 immune-mediated rash that does not resolve to ≤Grade 1 or baseline within 28 
days 
• Grade 2 rash covering > 30% BSA that does not resolve to ≤Grade 1 or baseline within 28 
days  
• Any grade of immune-mediated rash with bullous formation 
• Grade 3 immune-mediated neurotoxicity (excluding Guillain-Barre and myasthenia gravis) 
that does not resolve to ≤Grade 1 within 28 days 
• Grade 2 or 3 immune-mediated peripheral neuromotor syndrome (such as Guillain-Barre 
and myasthenia gravis) that does not resolve to ≤Grade 1 within 28 days or that exhibits 
signs of respiratory insufficiency or autonomic instability 
• Grade 3 immune-mediated myocarditis 
• Any symptomatic immune-mediated myocarditis that does not become asymptomatic 
within 3 days of initiating optimal medical management including systemic corticosteroids 
• Grade 2 or 3 immune-mediated myositis/polymyositis that does not resolve to Grade ≤1 
within 28 days of initiating optimal medical management including systemic 
corticosteroids or that exhibits signs of respiratory insufficiency regardless of optimal 
medical management 
• Immune-mediated increase in creatinine >3×ULN, or >3×baseline for patients with a 
baseline creatinine elevated above ULN 
 


 
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Any treatment-related toxicities that first occurred during the DLT period must be followed for 
resolution to determine if the event qualifies as a DLT as specified in the DLT criteria above. 
 
Immune-related AEs are defined as AEs of an immune nature (i.e., inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to designation 
as a DLT. 
 
Safety assessments will be performed on an ongoing basis based on a continuous reassessment 
method. The rate of Grade 3 or higher adverse events that fail to return to Grade 2 or less within 1 
week, and immune related adverse events that require high dose corticosteroids use will be factored 
into the decision about continued enrollment of patients in the trial. 
 
5.4 
Standard of Care Medications 
Package inserts and institutional standards for all aspects of administration of gemcitabine and 
cisplatin. This includes pre-medications, hydration, infusion times (windows), patient monitoring 
and side effect management.  
 
5.4 
Concomitant Medications 
 
5.4.1 Allowed Concomitant Medications 
All treatments the investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care. 
Concomitant medications or treatments (e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or supportive care, except for those medications 
identified as “prohibited,” are to be administered per site investigator. Best supportive care 
(including antibiotics, nutritional support, correction of metabolic disorders, optimal symptom 
control, and pain management [including palliative radiotherapy to non-target lesions, etc.]) should 
be used when necessary for all patients. Inactivated viruses, such as those in the influenza vaccine 
are permitted. 
 
5.4.2 Prohibited Concomitant Medications 
Patients should not receive any other systemic therapy for cancer unless specified in the protocol. 
If a patient needs palliative radiation therapy or other such local therapy for the treatment of limited 
areas of symptomatic disease or limited areas of progression, such as painful bone lesions, study 
therapy will be interrupted while receiving such therapy. Study therapy may be re-initiated after 
completion of such palliative therapy after discussion with the sponsor-investigator. Following 
are the prohibited medications.   
• Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than durvalumab and tremelimumab 
• Radiation therapy  
o NOTE: Palliative radiation therapy to symptomatic lesions or to the brain or limited 
areas of progression may be allowed at the investigator’s discretion. This must be 


 
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discussed with the sponsor investigator. It is important that at least one target lesion 
remains untreated with treatment other than study therapy. 
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
immune related adverse event or for use as a pre-medication before chemotherapy or to 
treat contrast related allergy or for treatment of COPD/asthma exacerbation.  The use of 
replacement doses of corticosteroids while on study is allowed. 
• Herbal and natural remedies which may have immune-modulating effects 
 
Subjects may receive other medications that the investigator deems to be medically necessary to 
manage the patient’s cancer such as bone modifying agents in patients with bone metastases and 
growth factors for management of neutropenia. 
 
5.5 
Contraception 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
 
5.5.1 Female patient of child-bearing potential 
Females of childbearing potential must be willing to abstain from heterosexual activity or agree to 
use a highly effective method of contraception from the time of informed consent until 180 days 
(durvalumab/tremelimumab) or 90 days (durvalumab) after treatment discontinuation. Females of 
childbearing potential randomized to Arm B must be willing to abstain from heterosexual activity 
or 
agree 
to 
use 
a 
highly 
effective 
method 
of 
contraception 
until 
180 
days 
(tremelimumab/durvalumab) or 90 days (durvalumab) after treatment discontinuation. Non-
sterilized male partners of a female patient must use male condom plus spermicide throughout this 
period. Cessation of birth control after this point should be discussed with the treating physician. 
Not engaging in sexual activity for the total duration of the drug treatment and the drug washout 
period is an acceptable practice; however, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. Female subjects should also refrain 
from breastfeeding throughout this period. 
 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
 
Women will be considered post-menopausal if they have been amenorrheic for 12 months without 
an alternative medical cause. The following age-specific requirements apply:  
• Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments 
and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-
menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
• Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 


 
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chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
 
5.5.2 Male subjects with a female partner of childbearing potential 
Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use a male condom plus spermicide from screening through 180 days (durvalumab/tremelimumab) 
or 90 days (durvalumab). Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods 
of contraception. Male subjects should refrain from sperm donation throughout this period. Female 
partners (of childbearing potential) of male subjects must also use a highly effective method of 
contraception throughout this period.  
 
5.5.3 Contraception Options 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly are described in the table below. 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; and triphasic combined oral 
contraceptive pills). 
 
Highly Effective Methods of Contraception (<1% Failure Rate) 
 
Barrier/Intrauterine methods 
Hormonal Methods 
• Copper T intrauterine device 
• Levonorgestrel-releasing 
intrauterine 
system 
(e.g., 
Mirena®)a 
• Etonogestrel implants: e.g. Implanon 
• 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 
a 
This is also considered a hormonal method 
 
5.5 
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 180 days following last infusion of tremelimumab. 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study as specified 
in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all grades), serious 
adverse events, and adverse events requiring study drug interruption or discontinuation as specified 
in Study Calendar & Evaluations.   


 
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6.1 
Dose Delays/Dose Modifications 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab are provided in the durvalumab/tremelimumab 
Toxicity Management Guidelines (TMGs). Please see Appendix 1.  
 
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. 
 
In addition, there are certain circumstances in which durvalumab and tremelimumab should be 
permanently discontinued. 
 
Following the first dose of study drug, subsequent administration of durvalumab can be 
modified based on toxicities observed as described in the Dosing Modification and Toxicity 
Management Guidelines. These guidelines have been prepared to assist the Investigator in the 
exercise of his/her clinical judgment in treating these types of toxicities. These guidelines apply to 
AEs considered causally related to durvalumab monotherapy and the durvalumab + tremelimumab 
regimen by the reporting investigator. 
 
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
sponsor-investigator. Broadly, if a patient develops an immune related adverse event that precludes 
further immunotherapy use but the patient remains fit to continue SoC and there is no evidence of 
clinical or radiologic progression, the patient may continue treatment in this protocol with SoC 
agents only based on SoA. All toxicities will be graded according to NCI CTCAE, Version 5.0.  
 
6.2 
Discontinuation from Protocol Therapy 
In addition to discontinuation from therapy related to toxicities as outlined in the section above, a 
subject will also be discontinued from protocol therapy and followed per protocol under the 
following circumstances outlined below.  The reason for discontinuation of protocol therapy will 
be documented on the electronic case report form (eCRF).   
• 
Documented disease progression per RECIST 1.1. Site investigator determines a change 
of therapy would be in the best interest of the subject 
• 
Subject requests to discontinue protocol therapy for any reason 
o If a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), 
the subject should be asked if he or she may still be contacted for further scheduled 
study assessments. The outcome of that discussion should be documented in both the 
medical records and in the eCRF. 
• 
Female subject becomes pregnant  
• 
Protocol therapy is interrupted for ≥ 28 days from the expected day of the next treatment.  
 
6.3 
Discontinuation from Protocol Activities 
If a subject decides to discontinue from all protocol activities and not just from protocol therapy, 
a final evaluation should be completed at the time of the subject’s protocol withdrawal. An 


 
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explanation of why the subject is withdrawing from the protocol will be recorded on the eCRF. A 
final assessment of adverse events will be recorded on the eCRF.  


 
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7. 
STUDY CALENDAR & EVALUATIONS 
 
Study Evaluation  
Cycle = 21 days 
Screening 
On Treatment 
Off Treatment 
Safety follow 
up visit10 
Cycle 1 
Cycle 2 -4 
Pre-Surgery 
Surgery 
-28 days 
Day 1 
± 3 days 
Day 8 
± 3 days 
Day 1 
± 3 days 
Day 8 
± 3 days 
Within 4-6 weeks 
30/90 days 
post last dose 
+ 7 days 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
 
D30 
Vital signs and ECOG Performance Status2 
X 
X 
X 
X 
X 
X 
 
D30 
ECG3 
X 
As clinically indicated 
 
 
 
AEs & concomitant medications11 
X 
X 
X 
X 
X 
X 
 
X 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
Complete Blood Cell Count with diff (CBC)4 
X 
X 
X 
X 
X 
X 
 
D30 
Comprehensive Metabolic Profile (CMP)4 
X 
X 
X 
X 
X 
X 
 
D30 
CA19-9 
X 
 
 
C3D1 
 
X 
 
 
Amylase and Lipase5 
X 
X 
 
X 
 
X 
 
 
Thyroid Function Testing5 
X 
X 
 
X 
 
X 
 
 
PT/PTT/INR 
X 
 
 
 
 
 
 
 
Hepatitis and HIV Testing5 
X 
 
 
 
 
 
 
 
Pregnancy test (serum or urine) (WOCBP)5 
X 
X 
 
X 
 
X 
 
 
Urinalysis5 
X 
X 
 
X 
 
X 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
CT of chest6 
X 
 
 
C3D1 
 
X 
 
 
CT or MRI of abdomen and pelvis6 
X 
 
 
C3D1 
 
X 
 
 
TREATMENT EXPOSURE7 
 
 
 
 
 
 
 
 
Tremelimumab 300 mg 
 
X 
 
 
 
 
 
 
Durvalumab 1500 mg 
 
X 
 
X 
 
 
 
 
Cisplatin 25 mg/m2 
 
X 
X 
X 
X 
 
 
 
Gemcitabine 1000 mg/m2 
 
X 
X 
X 
X 
 
 
 
SPECIMEN COLLECTION 
 
 
 
 
 
 
 
 
Archival Tumor Tissue8 
X 
 
 
 
 
 
 
 


 
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Study Evaluation  
Cycle = 21 days 
Screening 
On Treatment 
Off Treatment 
Safety follow 
up visit10 
Cycle 1 
Cycle 2 -4 
Pre-Surgery 
Surgery 
-28 days 
Day 1 
± 3 days 
Day 8 
± 3 days 
Day 1 
± 3 days 
Day 8 
± 3 days 
Within 4-6 weeks 
30/90 days 
post last dose 
+ 7 days 
Fresh Tumor Tissue8 
 
X8 
 
C3D1 
 
@ surgery or per fresh biopsy 
X8 
Peripheral Blood Samples8 
 
X 
 
C3D1 
 
X8 
 
D308 
FOLLOW-UP 
 
 
 
 
 
 
 
 
Survival Status, Subsequent Therapy 
 
 
 
 
 
 
 
X 
 
Key to Footnotes  
 
1: Medical History; other data to be obtained during this assessment includes a smoking history questionnaire and trial awareness question.  In 
addition, prior anti-cancer treatment should be documented including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery.  
Medical history will include diagnosis and staging such as pathology report and TNM staging documentation. AJCC staging manual v8 will be 
utilized. 
 
2: Vital signs to include temperature, pulse, respirations, blood pressure weight, and height (screening only) and ECOG performance status.   
 
3: Any clinically significant abnormalities detected require triplicate ECG results. During treatment, ECG should be performed as clinically indicated 
per site investigator discretion. 
 
4: CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen, LDH and albumin; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase. CBC and CMP may be performed 
more frequently if clinically indicated per site investigator discretion. Results for LFTs, electrolytes, full blood count and creatinine must be available 
before commencing an infusion (within 3 days) and reviewed by the treating physician or designee prior to dosing. 
 
5: Thyroid Function testing should be performed at screening, then every cycle. TSH will be obtained. T4 and T3 including free versus total testing 
is at the discretion of the site investigator. If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at 
Day 1. Hepatitis B surface antigen, hepatitis C antibodies, and HIV testing should be performed at screening. For women of childbearing potential 
(WOCBP): urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  Testing is required 7 days prior to initiation of study treatment but may be done on Day 1 if results are available 


 
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and reviewed by the treating physician or designee. During treatment, testing should be performed prior to each cycle. A urinalysis will be performed 
at screening then prior to each cycle. Results to include: bilirubin, blood, glucose, ketones, pH, protein, specific gravity and white blood cells. 
 
6: RECIST assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the chest, abdomen (including 
liver and adrenal glands) and pelvis. Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely.  
Additional anatomy should be imaged based on signs and symptoms of individual patients at baseline and follow-up.  Baseline assessments should 
be performed no more than 28 days before Cycle 1 Day 1 and ideally, should be performed as close as possible to and prior to the start of the study 
regimen.  The confirmatory scans should be performed preferably at the next scheduled imaging visit and no less than 4 weeks after the prior 
assessment of PD (in the absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at their next scheduled visit. The type of tumor imaging should 
remain consistent. Tumor imaging to be done after treatment discontinuation is at discretion of site investigator based on standard of care practice. 
If tumor assessments are available for subjects who have not yet experienced progressive disease (PD) at the time treatment is discontinued, the 
follow-up tumor evaluations will be documented in the eCRF until PD or death is confirmed, or until another treatment is initiated.  A window of ± 
7 days is allowed. 
 
7: See Section 5 for specifics regarding study treatment administration. 
 
8: Archival tissue is required if available. Tissue blocks are preferred but unstained cut slides acceptable. If archival tissue is not available, a 
newly obtained core or excisional biopsy of a previously unirradiated tumor lesion is required. A biopsy prior to Cycle 3 Day 1 is optional but 
strongly encouraged. For subjects undergoing surgery, sample of tissue is required. For subjects not undergoing surgery, a biopsy is optional and 
strongly encouraged. If a biopsy is performed at progression per standard of care, a sample of tissue is required for correlative analysis. See 
Correlative Laboratory Manual (CLM) for details regarding these samples. 
 
9: Blood samples will be collected for correlative analysis prior to treatment on (1) Cycle 1 Day 1, (2) Cycle 3 Day 1 and (3) after completion of 4 
cycles of treatment. The last sample may be obtained at the pre-surgical visit or the Day 30 safety visit. See Correlative Laboratory Manual (CLM) 
for details regarding these samples. 
 
10: Safety Follow Up: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, 
progression, or other reason) and should be performed 30 days (+ 7 days) after the last dose of study treatment. All AE (SAE) considered related to 
study drug(s) will be followed until resolution to ≤ Grade 1 or baseline, is deemed clinically insignificant, and/or until a new anti-cancer treatment 
starts, whichever occurs first. For those subjects undergoing surgery, the pre-surgery visit may include the Day 30 safety visit testing. The D90 
assessment of adverse events may be done via email, phone call or other avenues as appropriate. If either of these visits coincide with the pre-surgical 
or surgical visit, safety follow up may be done at that time. 


 
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11: It is recommended that patients are contacted 2 weeks after receiving the first 3 cycles of durvalumab (Cycle 1 Day 15 Cycle 2 Day 15, and 
Cycle 3 Day 15) to ensure early identification and management of toxicities. This may be performed by study staff via email, phone call or other 
avenues as appropriate.


 
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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
All samples described below should be collected Monday through Thursday. Additional details 
for all correlatives described below can be found in the Correlative Laboratory Manual (CLM). 
 
8.1 
Proposed Correlative Analyses 
• Determine changes in tumor mRNA gene expression pattern following treatment with 
combination platinum-based chemotherapy and doublet immunotherapy compared to 
pretreatment samples. (Correlatives priority # 1) 
• Assess changes in the phenotype of peripheral circulating CD4 Helper, CD4/FOxP3+ 
regulatory T cells and CD8 + T cells (Correlatives priority # 2) with a focus on activation 
vs exhaustion 
• Assess the change in the level of circulating soluble PDL1, HMGB1 and ATP secretion 
with therapy (Correlatives priority # 3) 
• The Ventana SP263 assay will be used for PDL1 testing. Testing should be restricted to 
the Ventana SP263 assay and should be performed in accordance with the package insert 
on the Ventana Benchmark platform (Ultra or XT). A positive PDL1 test is not required 
to screen and enroll patients to this study.  
• Blood for flow cytometry and ELISA, cfDNA and TCR analysis 
• Whole Exome Sequencing 
 
8.2 
Tissue Samples 
See the CLM for additional information regarding tissue for correlative analysis. 
 
8.2.1 Archival Tissue 
Formalin-fixed paraffin-embedded (FFPE) tumor tissue block ideally collected within 6 months 
prior to registration is required if available for the following analyses:  
• Diagnosis confirmation  
• Whole exome sequencing 
• Immunohistochemistry 
• PDL1 assessment if judged to be sufficient (in quality and quantity) 
• Nucleic acid extraction 
 
Tissue should ideally have been collected within 6 months prior to registration. A copy of the 
original pathology report must be provided, and the tissue collection date must be recorded so the 
sample age can be derived. Where archival tissue block is not available, 2 H& E stained slides and 
20-30 unstained, uncharged, air dried slides would be required.  
 
8.2.2 Fresh Tissue 
If archival tissue is not available or insufficient to perform the above analyses, a biopsy is required 
prior to treatment initiation. A biopsy is optional but strongly encouraged if clinically feasible after 
2 cycles of treatment/prior to Cycle 3 Day 1. After Cycle 4, tissue is required for correlative 
analysis from the surgical specimen. If the subject does not undergo surgery, a fresh biopsy is 
optional but strongly encouraged. If a biopsy is performed for standard of care purposes at 
progression, a sample is required for correlative analysis. A copy of the radiology and operative 
reports from the tissue removal procedure and the diagnostic anatomic pathology report is required 
to accompany all specimens. As much as possible, interventional radiology guided core- biopsies 


 
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are encouraged to enable collection of high-quality tissue with sufficient tumor content for the 
biomarker studies which are integral to this study. 
 
8.3 
Peripheral Blood  
Blood collection for correlative analysis is required and will occur prior to Cycle 1 Day 1 of 
treatment, after 2 cycles of treatment/prior to Cycle 3 Day 1 and after completion of Cycle 4. The 
following analyses are proposed: 
• Whole exome sequencing 
• phenotype of peripheral circulating CD4 Helper, CD4/FOxP3+ regulatory T cells and CD8 
+ T cells with a focus on activation vs exhaustion 
• level of circulating soluble PDL1, HMGB1 and ATP secretion with therapy  
• Blood for flow cytometry and ELISA, cfDNA and TCR analysis 
 
Please see the CLM for more information about blood biospecimen collection and banking 
 
8.4 
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific 
correlative research. The UAB tissue biorepository and the CCTS specimen processing and 
biorepository unit will manage the banked samples. Samples will be coded and banked indefinitely 
in and may be used for future unspecified cancer-related research.  
 
8.5 
Confidentiality of Biospecimens 
Samples will be identified by the subject’s study number assigned at the time of registration to the 
trial. Any material issued to collaborating researchers will be anonymized and only identified by 
the subject’s study number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. 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). 
 
9.1.1 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. 
 
9.2 
Non-measurable Lesions 
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/pneumonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 


 
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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 subject, these are preferred for selection as target lesions. 
 
9.3 
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. 
9.4 
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. 
 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 
45;2009:228-247) for special notes on the assessment 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 
 


 
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9.6 
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 tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits 
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 site 
investigator should prevail in such circumstances, and the progression status should be confirmed 
at a later time by the sponsor investigator. 
 
9.7 
Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all evaluated No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends on this determination, it is recommended that the 


 
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residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
10. 
DRUG INFORMATION 
 
10.1 
Tremelimumab 
Tremelimumab is an anti-CTLA-4 antibody being explored as a single-agent, and in combination 
with durvalumab, for the treatment of several malignancies. 
 
10.1.1 Supplier/How Supplied 
Tremelimumab will be supplied by AstraZeneca either as a 300-mg or a 25-mg vial solution for 
infusion after dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% 
weight/volume (w/v) polysorbate 80; it has a pH of 5.5 and density of 1.034 g/mL.  The nominal 
label-claim fill volume is 20.0 mL for the 300-mg vial and 1.25 mL for the 25-mg vial.  
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug 
product should be kept in original container until use to prevent prolonged light exposure. 
 
Tremelimumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free from or 
practically free from visible particles. 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
 
10.1.2 Preparation  
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 
 
Tremelimumab will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final tremelimumab concentration ranging from 0.10 to 10 mg/mL and delivered 
through an IV administration set with a 0.2- or 0.22-μm in-line filter. The IV bag size should be 
selected such that the final concentration is within 0.10 to 10 mg/mL. Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag.  
 
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. Do not co-administer other drugs 
through the same infusion line. 
 
In the event that either preparation time or infusion time exceeds the time limits a new dose must 
be prepared from new vials. Tremelimumab does not contain preservatives, and any unused portion 
must be discarded. 
 


 
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10.1.3 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to aseptic technique. 
 
Tremelimumab vials should be disposed at the site following local procedures for the disposal of 
anticancer drugs. 
 
10.1.4 Dispensing 
Tremelimumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Tremelimumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.1.5 Adverse Events 
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, diarrhea, 
enterocolitis and intestinal perforation), endocrine disorders (hypo and hyperthyroidism, 
hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), elevations in lipase and 
amylase and clinical manifestations of pancreatitis, other gastrointestinal events e.g. ulcerative 
colitis, dehydration, nausea and vomiting; hepatic events including hepatitis, and liver enzyme 
elevations; pneumonitis and ILD; nervous system events including encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barre and proximal muscle weakness; cytopenias including 
thrombocytopenia, anemia and neutropenia; infusion-related reactions, anaphylaxis, and allergic 
reactions; renal events including renal failure, acute kidney injury, nephritis, nephrotic syndrome, 
autoimmune nephritis and electrolyte abnormalities such as hypokalemia; autoimmune diseases 
including autoimmune arthritis, Sjogren's syndrome and giant cell temporal arteritis; 
hyperglycemia and diabetes mellitus; and pyrexia. For information on all identified and potential 
risks with tremelimumab please always refer to the current version of the tremelimumab IB. Using 
pooled data from monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% 
of patients) were diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, vomiting, dyspnea, 
constipation, cough, pyrexia, abdominal pain, decreased weight, headache, asthenia, and anemia. 
Approximately 16% of patients experienced an AE that resulted in permanent discontinuation of 
tremelimumab and approximately 45% of patients experienced an SAE. 
 
10.2 
Durvalumab 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 
on T cells and CD80 (B7.1) on immune cells (IC). Durvalumab has been engineered to reduce 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In vitro studies 
demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, 
resulting in their restored proliferation and release of interferon gamma IFNγ. 
 
Refer to the Investigator’s Brochure for additional information regarding this drug. 
 
10.2.1 Supplier/How Supplied 
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 (w/v) polysorbate 80; it has a pH of 6.0 and density 


 
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of 1.054 g/mL.  The label-claim fill nominal fill volume is 10.0 mL.  Investigational product vials 
are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.  
 
Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free from visible 
particles. 
 
Drug product should be kept in original packaging until use to prevent prolonged light exposure.  
Infusion solution must be allowed to equilibrate to room temperature prior to commencement of 
administration.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
 
10.2.2 Preparation  
The dose of durvalumab for administration must be prepared by the site’s designated 
investigational pharmacy 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 
 
A dose of 1500 mg will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/mL and delivered 
through an IV administration set with a 0.2- or 0.22-μm filter. Add 30 mL (i.e. 1500 mg) of 
durvalumab to the IV bag. The IV bag size should be selected such that the final concentration is 
within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the 
bag. 
 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.  
 
Do not co-administer other drugs through the same infusion line.  
 
The IV line will be flushed with a volume of IV diluent 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. 
 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared 
from new vials. Durvalumab does not contain preservatives, and any unused portion must be 
discarded. 
 
10.2.3 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to aseptic technique. 
 


 
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Durvalumab vials should be disposed at the site following local procedures for the disposal of 
anticancer drugs. 
 
10.2.4 Dispensing 
Durvalumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Durvalumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.2.5 Adverse Events 
Adverse events for durvalumab 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 
adverse events are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator Brochure. 
 
10.3 
Gemcitabine and Cisplatin 
All aspects of chemotherapy preparation and administration will be based on local practices and 
guidelines at investigation sites. Package insert for both drugs should be utilized for details.  
 
These drugs are commercially available. 
 
11 
ADVERSE EVENTS 
CTCAE v5 will be utilized to grade all adverse events. 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 
• An intercurrent illness or injury that impairs the well-being of the subject 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study regimen 
by the site investigator. 
 
Adverse Events (AEs) for malignant tumors reported during a study should generally be assessed 
as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 


 
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should be used. In certain situations, however, medical judgement on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the malignant 
tumor, the AE may not fulfill the attributes for being assessed as Serious, although reporting of the 
progression of the malignant tumor as an AE is valid and should occur. Also, some types of 
malignant tumors, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal cell carcinoma 
and Stage 1A1 cervical cancer removed via cone biopsy. 
 
The above instruction applies only when the malignant tumor event in question is a new malignant 
tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is being treated 
by the IP under study and is not the development of new or progression of existing metastasis to 
the tumor under study). Malignant tumors that – as part of normal, if rare, progression – undergo 
transformation (e.g., Richter's transformation of B cell chronic lymphocytic leukemia into diffuse 
large B cell lymphoma) should not be considered a new malignant tumor. 
 
11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
• Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional therapy, 
resection of primary tumor, or elective surgery, will not be considered serious adverse 
events. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
• Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 
× ULN may need to be reported as SAEs.  
 
11.1.3 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the study drug(s) and may require close monitoring and rapid communication by 
the site investigator to the sponsor-investigator. An AESI may be serious or non-serious. The rapid 


 
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reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of the study drug(s). If any AESI occurs in the course 
of the study, then the site investigators or other site personnel should report to the UAB CTNMO 
within 1 business day of becoming aware of the event. The CTNMO will report to AstraZeneca 
within 1 business day of becoming aware of the event.  
• Diarrhea / Colitis and intestinal perforation 
• Pneumonitis / ILD 
• hepatitis / transaminase increases 
• Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
• Rash / Dermatitis 
• Nephritis / Blood creatinine increases 
• Pancreatitis / serum lipase and amylase increases   
• Myocarditis 
• Myositis / Polymyositis 
• Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
• Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, haematological and rheumatological events, vasculitis, 
non-infectious meningitis and non-infectious encephalitis. It is possible that events with an 
inflammatory or immune mediated mechanism could occur in nearly all organs. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. Further information on these risks 
(e.g. presenting symptoms) can be found in the current version of the durvalumab and 
tremelimumab Investigator’s Brochures.  
 
More specific guidelines for their evaluation and treatment are described in detail in the Dosing 
Modification and Toxicity Management Guidelines (please see Appendix 1).  
 
11.1.4 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the pharmacological 
properties of the drug but are not specifically mentioned as occurring with the particular drug under 
investigation.   
 
11.1.5 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  


 
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Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
11.2 
Reporting 
 
11.2.1 Adverse Events  
• AEs will be recorded from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
• All AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 
or baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to UAB CTNMO 
• SAEs will be reported from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• SAEs include events related and unrelated to the study drug(s).  
• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
• SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
• All SAEs related to study drug(s) will be followed until resolution to ≤ Grade 1 or baseline 
and/or deemed clinically insignificant and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
The site will submit the completed SAE Submission Form to CTNMO within 1 business day of 
discovery of the event. The form will be submitted to the CTNMO electronically by email 
(pamdixon@uab.edu). The site investigator is responsible for informing the IRB and/or other local 
regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept within 
the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-up 
SAE Submission Form within a reasonable timeframe to the CTNMO electronically to 
pamdixon@uab.edu 
 
11.2.2.2 
Requirements for Reporting SAEs to AstraZeneca 


 
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The CTNMO will report all SAEs to AstraZeneca within 1 business day of receipt of the SAE 
Submission Form from a site. Follow-up information will be provided to AstraZeneca as it is 
received from site. Send SAE report and accompanying cover page by way of email to 
AstraZeneca’s designated mailbox:  AEMailboxClinicalTrialTCS@astrazeneca.com. 
 
 
11.6 
Other events requiring reporting 
 
11.6.1 Overdose 
Use of tremelimumab or durvalumab in doses in excess of that specified in the protocol is 
considered to be an overdose. There is currently no specific treatment in the event of overdose of 
tremelimumab, and possible symptoms of overdose are not established. An overdose with 
associated AEs will be recorded as the AE diagnosis or symptoms in the relevant eCRF. 
 
If an overdose of a study drug(s) occurs in the course of the study, then the site investigator or 
other site personnel will inform the CTNMO within 1 business day of becoming aware of the 
event. The UAB CTNMO will report the event to AstraZeneca within 1 business day of becoming 
aware of the event. 
 
11.6.2 Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
• Pregnancy discovered before the study subject has received any study drugs. 
• Pregnancy of a female partner of male subject, providing there is no restriction of male 
subject fathering a child. 
 
11.6.3 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study drug(s) should be 
discontinued immediately. Pregnancy itself is not regarded as an AE unless there is a suspicion 
that the study drug(s) 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 
outcome of 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 site investigator or other site personnel 
will inform the CTNMO within 1 business day of becoming aware of the event. The UAB 
CTNMO will report the event to AstraZeneca within 1 business day of becoming aware of the 
event.  
 
11.6.4 Paternal exposure  
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of study drug.  Pregnancy of the patient’s partner is not considered to 
be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date 
of the first dose until 90 days after the last dose of study drug should, if possible, be followed up 


 
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and documented.  
 
11.6.5 Reporting of deaths to AstraZeneca 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of study 
drug safety follow-up period must be reported to AstraZeneca as follows: 
• Death that is clearly the result of disease progression should be documented but should not 
be reported as an SAE. 
• Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the CTNMO within 24 hours and the CTNMO 
will report to AstraZeneca as a SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should assign 
main and contributory causes of death.  
• Deaths with an unknown cause should always be reported as a SAE.  
 
11.4 
Sponsor-Investigator Responsibilities  
The UAB CTNMO will send a SAE summary to the sponsor-investigator within 1 business day 
of receipt of SAE Submission Form from a site.  The sponsor-investigator will promptly review 
the SAE summary and assess for expectedness and relatedness.   
 
11.5    Responsibilities to FDA 
If an IND is assigned, CTNMO will manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of the sponsor-investigator. The UAB CTNMO will cross-
reference this submission to the AstraZeneca’s parent IND at the time of submission. A copy of 
these documents will be available to AstraZeneca upon request. 
 
For protocols conducted under an IND, CTNMO will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7- and 15-Day Reports, as 
well as an Annual Progress Report. A copy of these documents will be available to AstraZeneca 
upon request. 
 
For protocols exempt from the requirements of an IND, the above stated requirements are not 
applicable. The CTNMO will continue to facilitate compliance of applicable requirements for the 
sponsor-investigator in relation to this study. This includes but is not limited to 21 CFR 50.20 
informed consent, 21 CFR Part 56 IRB, and pertinent sections of the Public Health Service Act 
and FDAAA. 
 
11.6 
IND Safety Reports Unrelated to this Trial 
AstraZeneca will provide to the UAB CTNMO IND safety reports from external studies that 
involve the study drug(s) per their guidelines.  CTNMO will forward safety reports to the sponsor-
investigator who will review these reports and determine if revisions are needed to the protocol or 
consent. CTNMO will forward these reports to participating sites within 1 business day of 
receiving the sponsor-investigator’s review.  Based on the sponsor-investigator’s review, 
applicable changes will be made to the protocol and informed consent document (if required).  All 
IND safety reports will also be made available to sites via the EDC system.    
 


 
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Upon receipt from CTNMO, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
 
 


 
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12 
STATISTICAL METHODS 
 
12.1 
Study Design 
This is a multi-center open-label window of opportunity study. Objective response rate is the 
primary endpoint and safety assessment is a major secondary objective. The eligible population 
includes adults with resectable intrahepatic cholangiocarcinoma and high-risk features (borderline 
resectable). 
 
12.2 
Sample Size and Accrual 
The primary endpoint of this pilot trial is objective response rate (ORR). Twenty patients (20) will 
be treated in this study and we expect to accrue this number over 24 months across 4 institutions. 
Given the historical objective response rate of 25% and using one-sided exact test for single 
proportion, we will have 80% power to reject 25% ORR at α=0.05 when we observe ORR of 52% 
(Ho: Po=0.25 vs. Ha: Pa=0.52) from the study sample. For further investigation of the treatment 
with larger study (N=100), the presented ORR, 52%, will be detectible with 99% power at α=0.05 
and ORR, as less as 37%, will be detectible with 82% power at α=0.05.  
 
Patients who are incorrectly enrolled because they do not fully meet eligibility or deteriorate 
between screening and first study treatment can be replaced following consultation with the 
sponsor, and as long as the goal sample size has not been met. Withdrawn patients will only be 
replaced following a discussion with the investigator and sponsor-investigator and if it is thought 
to be feasible and the sample size has not been reached. Patients who discontinue from the study 
(related to toxicity, patient’s/physician’s choice or disease progression) after receiving at least 2 
cycles of study treatments will not be replaced. Patients who discontinue from the study before 
receiving at least 2 cycles of study treatment may be replaced. Such patients may be replaced 
following consultation between investigator and sponsor-investigator. The UAB CTNMO should 
be made aware of all communications regarding replacement of subjects. 
 
12.3 
Endpoints 
 
12.3.1 Primary Endpoint 
Evaluate the objective response rate (ORR) with the combination of platinum based (GemCis) and 
doublet immunotherapy (Durva/Trem) after 2 cycles of therapy and prior to surgical resection. 
 
12.3.2 Secondary Endpoints 
• Feasibility will be assessed by 3 criteria 
o Determine the rate of completion of preoperative therapy (4 cycles). 
o Determine the rate of R0 resection with combination chemotherapy and doublet 
immunotherapy. 
o Determine pathologic complete response rate (complete absence of foci of invasive 
adenocarcinoma). 
• Assess adverse events via NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
v5 during therapy with stopping rules for dose limiting toxicity per Inova et al [64].  
• Determine the time to complete enrollment of patients, and the number enrolled over a 24-
month period. 
 


 
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12.4 
Assessment of Safety 
Safety analysis will be performed on data from all patients who receive at least 1 dose of study 
drug (On cycle 1 Day 1). Safety assessments will be conducted in a continuous fashion based on 
a 6-week (2 cycles) DLT period and will impact the number of patients who are eventually enrolled 
in the study. At least 1 laboratory or vital sign measurement is required for inclusion in the analysis 
of each specific parameter. To assess a change from baseline, a baseline measurement is also 
required. 
 
Adverse events per CTCAE v 5.0 will be monitored and collected. Adverse events for safety 
analysis will be collected over 2 full cycles for each enrolled patient. This study will be set up to 
ascertain that adverse events are rare, and to end the study (before enrollment of the full sample 
size) in the event of an increased rate of adverse events. Twenty patients (20) are planned to be 
enrolled in this pilot study. 
 
12.5 
Assessment of Efficacy 
The analysis of the primary efficacy endpoint of ORR is based assessment of response after 
treatments. Based on this, only patients who receive at least 2 cycles of study treatment, and an 
on-treatment imaging scan will be included in the efficacy analysis set. 
 
12.6 
Data Analysis Plans 
 
12.6.1 Analysis Plans for Primary Objective 
See Section 12.2. 
 
12.6.2 Analysis Plans for Secondary Objectives 
The primary endpoint of the study is to evaluate the objective response rate (ORR) of the 
combination of doublet immunotherapy (durvalumab and tremelimumab) and platinum-based 
therapy (gemcitabine and cisplatin) in resectable intrahepatic cholangiocarcinoma with high risk 
features. Objective response rate (Complete Response + Partial Response) will be collected based 
on RECIST. The number of patients with an ORR will be reported as a percentage of the total 
number of patients analyzed for efficacy. Actual values and changes from baseline in tumor 
burden will be summarized by time-point.  
 
Patient characteristics at baseline will be collected and summarized by presenting descriptive 
statistics for overall and per site. Differences of the characteristics between patients with an 
objective response and those without will be summarized. Tumor response will be summarized 
using descriptive statistics. 
 
For continuous variables, means and standard deviations will be reported.  Student t-tests will be 
used to compare means where necessary.  Where appropriate, medians and interquartile ranges 
will be reported for presenting distribution of measures. Wilcoxon rank sum test will be considered 
as a nonparametric test of t-test.  Categorical measures will be presented as counts and percentages 
and will be compared using the z-test of proportions and χ2 test of association.  For rare outcomes 
such that the χ2 test of association is not appropriate, Fisher’s exact test will be used.  Results will 
be determined to be statistically significant when the accompanying statistical test yields a 
probability of 0.05 or less. 


 
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12.6.3 Analysis Plans for Exploratory Objectives 
Whole exome sequencing of biopsy specimens will be performed in conjunction with the Human 
Tissue Resource Center Pathology Core Facility and the laboratories of Dr Karina Yoon to assess 
baseline, therapy-induced changes, and status upon progression (where applicable). Flow 
cytometry will be performed on blood samples to determine baseline, and treatment-induced 
changes in the circulating immune cells (particularly CD4+, Helper T cells, CD8+ cytotoxic T 
cells) in the peripheral blood. Additionally, ELISA will be performed on serum samples to 
determine baseline, and treatment-induced changes in markers of immunogenic cell death 
(HMGB1, ATP) and circulating soluble PDL1 levels. The incidence of biomarkers will be 
summarized using descriptive statistics. Comparisons of molecular changes in tumors, and cellular 
and humoral changes in the blood pre and post treatment will be performed according to 
documentation of the efficacy endpoints (i.e. responders with a CR or PR vs non-responders with 
SD and PD). Exploratory analysis with Logistic regression will be used to assess if there are any 
biomarkers associated with clinical response or disease progression. All analysis will be 
exploratory. 
 
12.7 
Interim Analysis/Criteria for Stopping Study 
Sequential boundaries will be used to monitor dose-limiting toxicity rate. The accrual will be 
halted if excessive numbers of dose-limiting toxicities are seen relative to the number of patients 
treated on an ongoing basis (Table 1). Based on the calculations below, the probability of early 
stopping is based on the following assumptions; (α) = 0.05 and a dose-limiting toxicity rate (θ) = 
0.2. To summarize this approach, suppose that Zi (i=1,2) represents the standardized test statistic 
at the ith look (note that i=2 corresponds to the final look), then 
 
 
  
|Zi|  Bi, i=1,2 
Where B denote the corresponding boundary points (critical values) 
At first interim looks: 
Reject H0 if |Zi|  2.178 (i.e. p < 0.0294) 
Otherwise, continue 
At the final look: 
Reject H0 if |Zi|  2.178 (i.e. p < 0.0294) 
 
We recommend the use of Pocock-type boundary for two reasons.  First, it provides the best chance 
for early trial termination, because of its properties at the final stage of analysis if interim analysis 
were not planned.  Second, the Pocock-type boundary allow for early stopping at each interim 
analysis only in the presence of a large difference.  Since this study will simultaneously evaluate, 
a therapeutic model, the decision to stop the study early does little with regards to the logistics of 
the study, patients would still need to be followed in order to complete the study.   
 
Number 
of 
Patients, n 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
 
15 
 
16 
 
17 
 
18 
 
19 
 
20 
 
Boundary, bn 
 
- 
 
- 
 
3 
 
4 
 
4 
 
4 
 
5 
 
5 
 
5 
 
6 
 
6 
 
6 
 
7 
 
7 
 
7 
 
8 
 
8 
 
8 
 
9 
 
9 
 
 
 


 
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13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the University of Alabama at Birmingham (UAB) 
Comprehensive Cancer Center’s DSMP.  
 
Oversight activities include: 
• Review and process all adverse events requiring expedited reporting as defined in the 
protocol 
• Provide trial accrual progress, safety information and data summary reports to the sponsor-
investigator  
• Submit data summary reports to the lead institution Data Safety Monitoring Committee 
according to University of Alabama at Birmingham (UAB) Comprehensive Cancer 
Center’s DSMP. 
 
13.2 
University of Alabama at Birmingham (UAB) Comprehensive Cancer Center’s Data 
Safety Monitoring Committee 
Sites will provide the following for the University of Alabama at Birmingham (UAB) 
Comprehensive Cancer Center’s DSMC to review: 
• Adverse event summary report 
• Audit results if applicable 
• Data related to stopping/decision rules described in study design 
• Study accrual patterns  
• Protocol deviations 
 
The University of Alabama at Birmingham (UAB) Comprehensive Cancer Center’s DSMC will 
review study data every quarter.  Documentation of DSMC reviews will be provided to sponsor-
investigator and AstraZeneca.  Issues of immediate concern by the DSMC will be brought to the 
attention of the sponsor-investigator and other regulatory bodies as appropriate.   
 
13.3 
Data Quality Oversight Activities  
Remote validation of data will be completed on a continual basis throughout the life cycle of the 
study.  The CTNMO will provide data handling and edit checking services and queries will be 
transmitted to the site to address in a timely fashion. Corrections will be made by the study site 
personnel. 
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause audits may be performed as necessary. During onsite 
monitoring visits, source documents will be reviewed for verification of agreement with data 
entered into the EDC system.  It is important for the site investigator and their relevant personnel 
to be available for a sufficient amount of time during the monitoring visits or audit, if applicable. 
The site investigator and institution guarantee access to source documents by the UAB CTNMO 
or its designee. 
 
The trial site may also be subject to quality assurance audit as well as inspection by appropriate 
regulatory agencies.  


 
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13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is 
solely responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All results of 
primary and secondary objectives must be posted to CT.gov within a year of completion.  The 
sponsor-investigator has delegated responsibility to the CTNMO for registering the trial and 
posting the results on clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate trial locations and study site contact 
information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
Data will be collected through a web based clinical research platform (EDC system), a system 
compliant with Good Clinical Practices and Federal Rules and Regulations.  UAB Clinical Trial 
network and monitoring office (CTNMO) personnel will coordinate and manage data for quality 
control assurance and integrity. Select data will be collected and entered into the EDC system by 
study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source document. 
Select standard of care data will also be captured in the EDC system, according to study-specific 
objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should not 
be exported to third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without permission from the sponsor-investigator and the  UAB CTNMO. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities, the site investigator agrees to keep 
records, including the identity of all subjects (sufficient information to link records; e.g., hospital 
records), all original signed informed consent forms, copies of all source documents, and detailed 
records of drug disposition. All source documents are to remain in the subject’s file and retained 
by the site investigator in compliance with the site contract.  No records will be destroyed until the 
UAB CTNMO confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 


 
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secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, AstraZeneca, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance with local 
data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB before he or she 
can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to the 
IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration 
of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical Practice, and 
with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written information 
about the nature, purpose, possible risks and benefits of the study. Subjects must also be notified 
they are free to discontinue from the study at any time. The subject should be given the opportunity 
to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed informed 
consent form. A copy of the signed informed consent form must be given to the subject.  
 
 
 


 
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16 REFERENCES 
 
1. 
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APPENDIX 1 


 
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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 Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v5.0) 
General Considerations regarding 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 v5.0. 
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 immune-mediated 
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 
toGrade ≤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. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
− 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow. 
− 
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. 
− 
Some events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted in 
the guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., 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 (e.g., infliximab; 
also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 


 
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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 Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v5.0) 
General Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Note: For asymptomatic amylase or lipase levels of >2X ULN, hold study 
drug/study regimen, and if complete work up shows no evidence of pancreatitis, 
study drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
− 
Discontinuation of study drug/study regimen is not mandated for  
Grade 3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth. 
 
 
 
 
 


 
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Pediatric Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of the start of the immune-mediated event 
− 
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended. 
− 
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients. 
− 
The infliximab 5 mg/kg IV dose recommended for adults is the same as 
recommended for pediatric patients ≥ 6 years old.  For dosing in children 
younger than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring. 
 
 


 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
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 worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 


 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections)a 
− 
Consider Pulmonary and Infectious Disease consults. 
− 
Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., 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, as 
necessary, discussing with study physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections).a 
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.  


 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event, including 
perforation.  
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 over 
baseline per day; 
limiting instrumental 
ADL)  
(Colitis: abdominal 
pain; mucus or blood in 
stool) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can be 
resumed after completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup, such as 
imaging and/or colonoscopy, to confirm colitis and rule out 


 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
(Perforation: invasive 
intervention not 
indicated) 
perforation, and prompt treatment with IV methylprednisolone 
2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg 
IV methylprednisolone, promptly start immunosuppressives 
such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
− 
Consider, as necessary, discussing with study physician if no 
resolution to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
Grade 3 or 4 
(Grade 3 Diarrhea: 
stool frequency of ≥7 
over baseline per day; 
limiting self care ADL; 
Grade 4 Diarrhea: life 
threatening 
consequences) 
(Grade 3 Colitis: severe 
abdominal pain, fever; 
ileus; peritoneal signs; 
Grade 4 Colitis: life-
threatening 
consequences, urgent 
intervention indicated) 
(Grade 3 Perforation:   
invasive intervention 
Grade 3 
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
improve to Grade ≤1 within 14 days; 
study drug/study regimen can be resumed 
after completion of steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. If perforation is suspected,  
consult a surgeon experienced in abdominal surgery 
immediately without any delay . 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 


 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
indicated;  
Grade 4 Perforation: 
life-threatening 
consequences; urgent 
intervention indicated) 
 


 
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Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any  Grade 
 
General Guidance 
For Any Grade 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
(AST or ALT >ULN 
and ≤3.0×ULN if 
baseline normal, 1.5-
3.0×baseline if baseline 
abnormal; and/or TB 
>ULN and ≤1.5×ULN 
if baseline normal, 
>1.0-1.5×baseline if 
baseline abnormal) 
• 
No dose modifications. 
• 
If it worsens, then treat as  Grade 2.  
− 
Continue LFT monitoring per protocol. 
Grade 2  
(AST or  
ALT >3.0×ULN and 
≤5.0×ULN if baseline 
normal, >3-5×baseline 
if baseline abnormal; 
and/or  
TB >1.5×ULN and 
≤3.0×ULN if baseline 
normal, >1.5- 
3.0×baseline if baseline 
abnormal) 
• 
Hold study drug/study regimen dose 
until resolution to  Grade≤1. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to  Grade≤1, 
resume study drug/study regimen 
after completion of steroid taper. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) 
until elevations of these are improving or resolved. 
− 
If no resolution to ≤Grade 1 in 1 to 2 days, consider, as 
necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 


 
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Grade 3 
 (AST or  
ALT >5.0×ULN and 
≤20×ULN if baseline 
normal, >5-20× 
baseline if baseline 
abnormal; and/or  
TB >3.0×ULN  and  
≤10.0×ULN if baseline 
normal, >3.0-10.0× 
baseline if baseline 
abnormal) 
 
 
Grade 4 
(AST or ALT 
>20×ULN if baseline 
normal, >20×baseline if 
baseline abnormal; 
and/or  
TB >10×ULN if 
baseline normal, 
>10.0×baseline if 
baseline abnormal)   
For elevations in transaminases ≤8×ULN, 
or elevations in TB ≤5×ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade≤1 
• Resume study drug/study regimen if 
elevations downgrade to  Grade≤1 
within 14 days and after completion 
of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade≤1 within 
14 days. 
For elevations in transaminases >8×ULN 
or elevations in bilirubin >5×ULN, 
permanently discontinue study drug/study 
regimen. 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria (AST and/or ALT >3×ULN + 
bilirubin >2×ULN without initial findings 
of cholestasis [i.e., elevated alkaline P04] 
and in the absence of any alternative 
cause).b 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Request Hepatology consult, and perform abdominal workup 
and imaging as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis.  
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 
Any Elevations of 
AST, ALT, or TB as 
Described Below 
General Guidance 
 
For Any Elevations Described: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver 
cirrhosis [e.g., portal vein thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral load 
− 
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold 
− 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as 
above 
 Isolated AST or ALT 
>ULN and ≤5.0×ULN, 
whether normal or 
elevated at 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 
 
 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients  


 
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Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal 
at baseline 
 
Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if 
elevated >ULN at 
baseline 
 
• 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤5.0×ULN. 
• 
If toxicity worsens, then treat as 
described for elevations in the rows 
below. 
If toxicity improves to AST or ALT 
≤5.0×ULN, resume study drug/study 
regimen after completion of steroid taper. 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) 
until elevations of these are improving or resolved. 
− 
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion. 
− 
Consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and investigator 
suspects toxicity to be immune-mediated AE, recommend to 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV methylprednisolone 2 
to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider additional 
abdominal workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting immunosuppressives 
(i.e., mycophenolate mofetil).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should 
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 within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to AST or ALT 
≤5.0×ULN within 14 days 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria, in the absence of any alternative 
cause.b 
− 
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, as necessary, discussing with study physician. 
− 
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it 
has not been done already) and promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil). Discuss 
with study physician if mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 


 
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Isolated AST or ALT 
>20×ULN, whether 
normal or elevated at 
baseline 
 
Permanently discontinue study drug/study 
regimen. 
 
Same as above  
(except would recommend obtaining liver biopsy early) 
 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise 
- 
For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT 
>2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and 
≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to changes 
in renal function (e.g., routine urinalysis, elevated serum BUN 
and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, or proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
 
 


 
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Grade 1 
(serum creatinine  
>ULN to 1.5×ULN) 
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. 
− 
If baseline serum creatinine is elevated above normal, and there 
is a rise to > 1 to 1.5 × baseline, consider following 
recommendations in this row.  
Grade 2 
(serum creatinine >1.5 
to 3.0×baseline; >1.5 to 
3.0×ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
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. 


 
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>3.0×baseline; >3.0 to 
6.0×ULN) 
 
(Grade 4: serum 
creatinine >6.0×ULN) 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
Rash or Dermatitis 
(including Pemphigoid) 
Any Grade 
(refer to NCI CTCAE 
v 5.0 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED IF SUSPECT STEVENS-
JOHNSON SYNDROME OR TOXIC EPIDERMAL 
NECROLYSIS. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Obtain Dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
− 
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, consider, as necessary, 
discussing with study physician and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. If > 30% body surface area is involved, consider 
initiation of systemic steroids promptly. 
− 
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs. 


 
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Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study drug/study 
regimen. 
 
For Grade 4 (or life-threatening): 
Permanently discontinue study drug/study 
regimen. 
 
For Grade 3 or 4 (or life-threatening): 
− 
Consult Dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v5.0 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing with study physician. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For asymptomatic elevations in serum amylase and lipase 
>ULN and <3×ULN, corticosteroid treatment is not indicated 
as long as there are no other signs or symptoms of pancreatic 
inflammation. 
− 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 


 
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or diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
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 
consultation of an endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
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 ≤10 mg/day 
or equivalent. 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
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 (e.g., hydrocortisone, sex hormones). 
− 
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 study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated. 


 
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Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) are 
controlled.  
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
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 ≤10 mg/day 
or equivalent. 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. Hospitalization 
recommended. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v5.0 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with Neurology consult as 
appropriate. 
− 
 


 
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Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
− 
Treat mild signs/symptoms as Grade 1 (e.g.  loss of deep 
tendon reflexes or paresthesia) 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade ≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade ≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be resumed 
once event improves to Grade ≤1 and 
after completion of steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Obtain Neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with study physician. 
− 
Obtain Neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly treat 
with additional immunosuppressants (e.g., IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 


 
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a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., 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 (e.g., 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 
(Guillain-Barre [GB]:  
mild symptoms) 
(Myasthenia gravis 
[MG]: asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated)    
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a Neurology consult. 
Grade 2 
(GB: moderate 
symptoms; limiting 
instrumental ADL) 
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 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a Neurology consult 


 
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(MG: moderate; 
minimal, local or 
noninvasive 
intervention indicated; 
limiting age-
appropriate 
instrumental ADL) 
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. Such 
decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Grade 3 or 4 
(Grade 3 GB: severe 
symptoms; limiting self 
care ADL;  
Grade 4 GB: life-
threatening 
consequences; urgent 
intervention indicated; 
intubation) 
(Grade 3 MG: severe or 
medically significant 
For Grade 3: 
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 or 
autonomic instability. 
 
 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with study physician. 
− 
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. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. 


 
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but not immediately 
life-threatening; 
hospitalization or 
prolongation of existing 
hospitalization 
indicated; limiting self 
care ADL;  
Grade 4 MG: life-
threatening 
consequences; urgent 
intervention indicated) 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
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). A 
Cardiology consultation should be obtained early, with prompt 
assessment of 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) 


 
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Grade 1 
(asymptomatic or mild 
symptoms*; clinical or 
diagnostic observations 
only; intervention not 
indicated) 
*Treat myocarditis with 
mild symptoms as 
Grade 2. 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up as 
clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms 
with moderate activity 
or exertion) 
 (Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; inter-
vention indicated; new 
onset of symptoms*) 
(Grade 4: Life-
threatening conse-
quences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support)) 
 
* Consider “new onset 
of symptoms” as 
referring to patients 
with prior episode of 
myocarditis. 
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures including 
a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 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 every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 


 
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Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
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 new-onset 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 study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of 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. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
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 study physician. 


 
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Grade 2 
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
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. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 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 3 to 5 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 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
Grade 3 or 4 
(Grade 3: pain 
associated with severe 
weakness; limiting self-
care ADLs 
 
Grade 4:  life-
threatening 
consequences; urgent 
intervention indicated) 
For Grade 3: 
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. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 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 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 


 
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aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
 


 
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Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
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 (e.g., 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 (e.g., 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 (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 
 
 
 


 
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Non–Immune-Mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
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. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.