Conditions: Esophageal Cancer
Keywords: Durvalumab MEDI4736 PD-L1 inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
This is a phase II, open-label, single arm, single-stage study. A total of 23 evaluable patients will be enrolled. If total number of patients free of disease relapse at 1 year is less than or equal to 15, the drug would not be considered for further study in this setting. After six patients are treated with at least one dose of study drug, they will be observed for a minimum of 60 days. During the 60-day observation period, further accrual will be halted to evaluate "unacceptable toxicities warranting early closure of the trial" defined as:

* Any definitive durvalumab-related death. A durvalumab-related death will be continuously monitored throughout the trial and the trial will be suspended for re-evaluation whenever such an event is confirmed.
* Any unexpected and previously unreported grade 4 toxicities definitely related to durvalumab.

Detailed description:
OUTLINE: This is a multi-center trial.

INVESTIGATIONAL TREATMENT:

Subjects will receive durvalumab 1500 mg IV every 4 weeks (1 cycle) for a maximum 13 doses (12 months), or until unacceptable toxicities or disease recurrence.

The following baseline labs must be completed within 28 days prior to registration for protocol therapy:

Hematopoietic:

* White blood cell count (WBC) \> 3 K/mm\^3
* Hemoglobin (Hgb) \> 9 g/dL. Transfusion is allowed, if needed, since patients are post esophagectomy.
* Platelets \> 100 K/mm\^3
* Absolute neutrophil count (ANC) ≥ 1.5 K/mm\^3

Renal:

* Calculated creatinine clearance of \>/= 40 cc/min using the Cockcroft-Gault formula or by 24-hour urine collection.

Hepatic:

* Bilirubin ≤ 1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST, SGOT) \</= 2.5 x ULN
* Alanine aminotransferase (ALT, SGPT) \</= 2.5 x ULN

Arms:
arm 1: Durvalumab 1500 mg IV every 4 weeks (1 cycle) for a maximum 13 doses (12 months), or until unacceptable toxicities or disease recurrence.

Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: 1500 mg IV every 4 weeks (1 cycle) for a maximum 13 doses (12 months), or until unacceptable toxicities or disease recurrence.

Protocol document:
Prot_SAP_000.pdf: 
  
Clinical Study Protocol 
 
 
 
 
BTCRC-ESO14-012 
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Protocol Title 
A Phase II Study Evaluating Safety and Efficacy of Durvalumab (MEDI4736) 
Following Multi-Modality Therapy in Esophageal Cancer: Big Ten Cancer Research 
Consortium BTCRC-ESO14-012 
 
 
Sponsor-Investigator 
Shadia Jalal, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
 
Co-Investigators  
Hirva Mamdani, MD 
Nasser Hanna, MD 
Kenneth Kesler, MD 
Sunil Badve, MD 
Milan Radovich, PhD 
 
 
Statistician 
Susan Perkins, PhD 
 
 
Trial Supported by  
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca PLC 
(ESR-14-10654) 
 
Trial Management by 
Big Ten CRC Administrative Headquarters at Hoosier Cancer Research Network 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
Investigational New Drug (IND) Application #   
129416 
 
 
 
Initial Protocol Version Date: 23DEC2015 
 
Amendment Version Date: 
15MAR2017 
19FEB2018  
07DEC2018 (IU only) 
24JAN2019 
09OCT2019 (current) 


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PROTOCOL SIGNATURE PAGE 
 
A Phase II Study Evaluating Safety and Efficacy of Durvalumab (MEDI4736) Following Multi-
Modality Therapy in Esophageal Cancer:  
Big Ten Cancer Research Consortium BTCRC-ESO14-012 
 
VERSION DATE:  09OCT2019 
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, or the applicable laws and regulations of the country of the 
study site for which I am responsible, 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 ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
 
 
       Date 
 
 
____________________________________ 
 Investigator Name (printed) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL TO BIG TEN CRC  
ADMINISTRATIVE HEADQUARTERS  
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to BRTCRC Administrative Headquarters and keep a 
record for your files. 


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STUDY SYNOPSIS 
 
TITLE 
A Phase II Study Evaluating Safety and Efficacy of Durvalumab 
(MEDI4736) Following Multi-Modality Therapy in Esophageal 
Cancer 
SHORT TITLE 
A Phase II Study of Durvalumab (MEDI4736) in Esophageal Cancer 
PHASE  
II 
OBJECTIVES 
Primary Objective:  
 To determine if postoperative adjuvant therapy with durvalumab 
improves 1 year relapse free survival (RFS) compared to historical rates 
in patients with persistent esophageal cancer following neoadjuvant 
chemoradiotherapy and esophagectomy  
 
Secondary Objectives:  
 To assess the toxicity and tolerability of durvalumab following 
trimodality therapy in patients with esophageal cancer. 
 
Correlative Objectives:  
 To assess changes in PD-L1 expression with chemoradiotherapy in 
esophageal cancer.  
 To analyze possible predictive biomarkers of 1 year RFS including PD-
L1 expression (at diagnosis and in residual disease) in tumor cells and 
tumor infiltrating lymphocytes (by histology and gene expression 
analysis – by pathway analysis and CIBERSORT), both within the 
tumor and in surrounding connective tissue. 
 To assess the Immunoscore (based on numeration of lymphocyte 
populations - CD3/CD45RO, CD3/CD8, CD8/CD45RO) – within the 
center and invasive margins of the tumor – and correlate with 1 year 
RFS. 
 To analyze the correlation between changes in circulating tumor cell 
numbers in response to PD-L1 inhibition and 1 year RFS in patients 
with residual esophageal cancer. 
OUTCOME 
MEASURES 
 Primary: Relapse free survival (RFS) at 1 year 
 Secondary: Incidence and severity of adverse events overall and related 
to the study drug.  
 Exploratory outcomes as above.
STUDY DESIGN 
Phase II, open-label, single arm, single-stage study. A total of 23 evaluable 
patients will be enrolled (26 total to account for 10% unevaluable). If total 
number of patients free of disease relapse at 1 year is less than or equal to 15, 
the drug would not be considered for further study in this setting. To improve 
accuracy for estimating the primary endpoint (1 year RFS) with a 95% 
confidence interval, an additional 11-16 patients beyond the initial planned 
23 evaluable will be enrolled for a target of 34-39 enrolled to have at least 34 
patients evaluable for 1 year RFS.  


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After six patients are treated with at least one dose of study drug, they will 
be observed for a minimum of 60 days. During the 60-day observation 
period, further accrual will be halted to evaluate "unacceptable toxicities 
warranting early closure of the trial" defined as:  
1) Any definitive durvalumab-related death. A durvalumab-related death 
will be continuously monitored throughout the trial and the trial will be 
suspended for re-evaluation whenever such an event is confirmed. 
2) Any unexpected and previously unreported grade 4 toxicities definitely 
related to durvalumab. 
 
If such events are observed in one subject, the DSMB will discuss and 
provide recommendations to the sponsor-investigator. If such events are 
observed in two or more subjects, the trial will be suspended for re-
evaluation. 
 
Pneumonitis of grade 3 and 4 will be continuously monitored. An overall 
rate of 20% or above would be considered unacceptable. If the probability 
of the grade 3/4 pneumonitis rate being less than 20% drops below 0.1, the 
trial will be suspended for re-evaluation.
ELIGIBILITY 
CRITERIA  
Inclusion Criteria: 
- 
Esophageal cancer with persistent residual disease in the surgical 
sample following neoadjuvant concurrent chemoradiotherapy 
(carboplatin and paclitaxel or cisplatin and 5-FU) followed by surgical 
resection.  
- 
Must have had R0 resection (defined as resection with negative 
margins) 
- 
Minimum of 1 month and maximum of 3 months from surgical 
resection with no evidence of disease recurrence at the time of 
enrollment 
- 
ECOG Performance status 0-1 
- 
Adequate bone marrow, renal and hepatic function 
- 
Must have adequately recovered from chemoradiation and surgery 
Exclusion Criteria: 
- 
Prior therapy with a PD-1, PD-L1, or CTLA-4 inhibitor or cancer-
specific vaccine therapy 
- 
Patients with R1 resection (defined as positive margins after resection) 
or R2 resection (defined as presence of macroscopic residual disease 
after resection) 
- 
Evidence of active autoimmune disease requiring systemic treatment 
within preceding 3 months or a documented history of clinically severe 
autoimmune disease, or a syndrome that requires ongoing use of 
systemic steroids or immunosuppressive agents. Exceptions to this rule 
include vitiligo, resolved childhood asthma/atopy, requirement of 
intermittent bronchodilators or local steroid injections, hypothyroidism 
stable on hormone replacement, Sjogren’s syndrome. 
- 
Presence of interstitial lung disease or history of pneumonitis requiring 
treatment with corticosteroids


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- 
Patients with diagnosis of immunodeficiency or those receiving chronic 
systemic corticosteroid therapy or other immunosuppressive therapy 
(except inhaled steroids) within 28 days of the first dose of study drug 
- 
History of psychiatric illness/social situations that would limit 
compliance with study requirements. 
- 
Clinically significant infections as judged by the treating investigator. 
Clinically significant is defined as an active infection requiring IV 
antibiotics 
- 
Known HIV infection or chronic hepatitis B or C. 
STATISTICAL 
CONSIDERATIONS 
Null Hypothesis: 1 year RFS with postoperative adjuvant durvalumab 
therapy in patients with persistent esophageal cancer following neoadjuvant 
chemoradiotherapy and esophagectomy is 50% or less. 
Alternative Hypothesis: 1 year RFS with postoperative adjuvant 
durvalumab therapy in patients with persistent esophageal cancer following 
neoadjuvant chemoradiotherapy and esophagectomy is 75% or greater. 
Acceptable Type I (alpha) error: 5% 
Acceptable Type II (beta) error: 20% 
Power: 80% 
Phase II, open label, single arm, single-stage study.  
TOTAL  
NUMBER OF 
SUBJECTS  
Total n=39, 34 efficacy evaluable and allowing for up to 5 unevaluable. 
Subjects who receive less than 6 months of durvalumab for reasons 
unrelated to disease progression or toxicity will be replaced. 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 18 months 
ESTIMATED 
STUDY 
DURATION  
Estimated 39 months 
 
 
 


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INDEX  
 
SECTION                                                                                                                 
PAGE 
 
SCHEMA .......................................................................................................................................... 8 
1. 
BACKGROUND & RATIONALE .................................................................................. 9 
2. 
OBJECTIVES, ENDPOINTS AND OUTCOME MEASURES ................................. 15 
2.1. 
Objectives ......................................................................................................................... 15 
2.2. 
Endpoints ......................................................................................................................... 16 
2.3. 
Outcome Measures .......................................................................................................... 16 
3. 
ELIGIBILITY CRITERIA ............................................................................................ 17 
3.1. 
Inclusion Criteria ............................................................................................................ 17 
3.2. 
Exclusion Criteria ........................................................................................................... 18 
4. 
SUBJECT REGISTRATION ......................................................................................... 19 
5. 
TREATMENT PLAN ..................................................................................................... 20 
5.1. 
Pre-medication ................................................................................................................. 20 
5.2. 
Drug Administration ....................................................................................................... 20 
5.3. 
Supportive Care: ............................................................................................................. 20 
5.4. 
Concurrent Therapy ....................................................................................................... 20 
5.5. 
Restrictions during the study ......................................................................................... 21 
6. 
DOSE MODIFICATIONS ............................................................................................. 22 
6.1. 
Dose Modifications .......................................................................................................... 22 
7. 
STUDY CALENDAR & EVALUATIONS ................................................................... 50 
7.1. 
Screening .......................................................................................................................... 52 
7.2. 
On Treatment .................................................................................................................. 52 
7.3. 
Protocol therapy discontinuation ................................................................................... 54 
7.4. 
Safety Follow-up: 30 days (±7 days) after last dose of protocol therapy ................... 54 
7.5. 
At Recurrence: ................................................................................................................. 55 
7.6. 
Follow-up.......................................................................................................................... 55 
8. 
CRITERIA FOR DISEASE EVALUATION ............................................................... 55 
9. 
BIOLOGICAL CORRELATIVES ................................................................................ 57 
10. 
DRUG INFORMATION ................................................................................................ 59 
10.1. 
Drug Names: .................................................................................................................... 59 
10.2. 
Drug Class:....................................................................................................................... 59 
10.3. 
Formulation, Packaging and Storage ............................................................................ 59 
10.4. 
Availability and Distribution.......................................................................................... 59 
10.5. 
Preparation ...................................................................................................................... 60 
10.6. 
Administration ................................................................................................................. 60 
10.7. 
Precautions ....................................................................................................................... 60 
10.8. 
Side Effects ....................................................................................................................... 60 
11. 
ADVERSE EVENTS ....................................................................................................... 61 
11.1. 
Definitions ........................................................................................................................ 61 
11.2. 
Reporting.......................................................................................................................... 65 
11.3. 
IND Safety Reports Unrelated to This Trial ................................................................. 68 
12. 
STATISTICAL CONSIDERATIONS .......................................................................... 68 
12.1. 
General Considerations .................................................................................................. 68 
12.2. 
Study Design .................................................................................................................... 69 


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12.3. 
Definition of Primary Endpoint ..................................................................................... 69 
12.4. 
Definitions of Secondary Endpoints .............................................................................. 69 
12.5. 
Definitions of Correlative Endpoints ............................................................................. 69 
12.6. 
Sample Size/Accrual/Study Duration/Replacement Rules .......................................... 69 
12.7. 
Criteria for Stopping the Study ..................................................................................... 70 
12.8. 
Analysis Datasets ............................................................................................................. 70 
12.9. 
Subject Characteristics and significant protocol violations ........................................ 70 
12.10. 
Concomitant Medication ................................................................................................ 70 
12.11. 
Disposition ........................................................................................................................ 70 
12.12. 
Analysis Plan for Primary Objectives/Aims ................................................................. 71 
12.13. 
Analysis Plan for Secondary Objectives/Aims .............................................................. 71 
12.14. 
Analysis Plan for Correlative/Exploratory Objectives ................................................ 71 
13. 
TRIAL MANAGEMENT ............................................................................................... 71 
13.1 
Data and Safety Monitoring Plan (DSMP) ................................................................... 71 
13.2 
Data Quality Oversight Activities .................................................................................. 73 
13.3 
Compliance with Trial Registration and Results Posting Requirements ................... 73 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................... 74 
14.1 
Case Report Forms and Submission .............................................................................. 74 
14.2 
Record Retention ............................................................................................................. 74 
14.3 
Confidentiality ................................................................................................................. 74 
14.4 
Changes to the Protocol and Informed Consent .......................................................... 75 
15 
ETHICS ............................................................................................................................ 75 
15.1 
Ethics Review ................................................................................................................... 75 
15.2 
Ethical Conduct of the Study ......................................................................................... 76 
15.3 
Informed Consent Process .............................................................................................. 76 
16 
REFERENCES ................................................................................................................ 77 


 
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SCHEMA 
 
A Phase II Study Evaluating Safety and Efficacy of Durvalumab (MEDI4736) Following  
Multi-modality Therapy in Esophageal Cancer:  
Big Ten Cancer Research Consortium BTCRC-ESO14-012 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Durvalumab 1500 mg 
Every 4 weeks  
Up to 12 months (13 doses) 
No disease 
recurrence 
Disease Assessment every 3 months  
Significant toxicity or 
non-PD discontinuation 
Continue treatment up 
to 12 months (13 doses) 
Discontinue 
treatment 
Patients with locally advanced esophageal cancer without distant metastasis who have received 
neoadjuvant concurrent chemoradiation followed by surgery and have persistent residual 
disease in the surgical sample (esophagus or lymph node or both), including patients with 
marked (<10% residual tumor), moderate (10-50% residual tumor) or no definite response 
(>50% residual tumor).  
Follow for relapse free 
survival for 1 year after 
treatment discontinuation. 
Disease 
recurrence  
Discontinue 
treatment 


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1. BACKGROUND & RATIONALE 
 
1.1 General Background: 
Esophageal cancer has been recently described as ‘the silent epidemic’ because of its rapidly rising 
incidence. It is the 6th leading cause of cancer related mortality in men in the United States (1). 
Approximately 16,980 new cases and 15,590 deaths are estimated to occur from esophageal cancer 
in U.S. in 2015, with a 5- year survival rate of 17.9% (2). Multiple factors contribute to the poor 
prognosis associated with esophageal cancer. These include a) the advanced stage at the time of 
diagnosis b) the complex biology of the disease with large mutational burden, and c) resistance to 
currently available therapies (3). Two-thirds of the patients with esophageal cancer have locally 
advanced disease. A standard of care for fit patients with locally advanced esophageal cancer is tri-
modality therapy with concurrent platinum-based chemotherapy and ionizing radiation followed by 
surgical resection. With this approach, only about 29% of the patients achieve a complete pathologic 
response (4). The majority of patients with persistent residual disease noted on surgical specimen 
will recur leading to a poor prognosis with median survival of 12 months. No post-operative therapy 
has been shown to improve outcomes in this patient population. With its grim prognosis, there is a 
pressing need for novel agents in the treatment of esophageal cancer that can decrease the risk of 
relapse following tri-modality therapy. 
 
Chemotherapy agents with activity in locally advanced esophageal cancer are limited to 5 classes 
of agents. These include taxanes (docetaxel or paclitaxel), fluoropyrimidines (capecitabine or 5-
FU), platinums (oxaliplatin, carboplatin, cisplatin), topoisomerase I inhibitors (irinotecan) and 
anthracyclines (epirubicin). Standard chemotherapy regimen in combination with ionizing radiation 
for the treatment of locally advanced esophageal cancer is either weekly carboplatin and paclitaxel 
or cisplatin and 5-FU (4, 5). Outcomes with these regimens are comparable. There is currently no 
proven role for adjuvant chemotherapy in esophageal cancer patients following tri-modality therapy. 
 
The importance of an intact immune surveillance in controlling outgrowth of neoplastic processes 
has been known for decades (6). Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies (7-
13). In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid 
tumors (14). Similar correlation has been found in esophageal squamous cell carcinoma as well (15). 
The programmed cell death protein 1 (PD-1) receptor-ligand interaction is a major pathway hijacked 
by tumors to suppress host immune response to the tumor. The normal function of PD-1, expressed 
on the cell surface of activated T- cells under physiologic conditions, is to down-modulate unwanted 
or excessive immune responses especially in peripheral tissues, including autoimmune reactions. 
PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which 
has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2) (16). PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic 
tail which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif 
(ITIM) and an immune-receptor tyrosine- based switch motif (ITSM). Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which 
are involved in the CD3 T-cell signaling cascade (16-19). The mechanism by which PD-1 down 


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modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate 
an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells (20). The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of 
cell types, including non-hematopoietic tissues as well as in various tumors. PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas 
PD-L2 is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues (16, 21). 
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor 
(18, 22). Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor including esophageal cancer. PD-1 
has also been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (23). 
It has also been shown that blockade of PD-1 pathway leads to T cell activation and cytokine release 
(24).  
This evidence suggests that the PD-1/PD-L1 pathway plays a critical role in evasion of host immune 
system by tumor and should be considered as an attractive target for therapeutic intervention. Recent 
data have shown that inhibition of the PD-1 pathway leads to durable tumor regression (25). Several 
immune checkpoint inhibitors in the form of monoclonal antibodies to PD-1 and PD-L1 are 
currently being tested in various malignancies, both in combination with other therapies and as 
single agents. Growing clinical evidence demonstrates activity of PD-1 pathway inhibitors in 
esophageal cancer including pembrolizumab (PD-1 inhibitor) and durvalumab (MEDI4736). 
Durvalumab is a fully human IgG1 monoclonal antibody against PD-L1 with preliminary data 
demonstrating activity in a variety of tumors including esophageal cancer (26, 27).  
The dynamic PD-1 pathway is impacted by various cancer directed treatment modalities including 
ionizing radiation. Ionizing radiation induces a local inflammatory response that enhances the 
infiltration of tumor-specific T cells and simultaneously upregulates PD-1/PD-L1 pathway in the 
tumor microenvironment thereby inhibiting immune activation. This upregulation limits some of 
the radiation induced toxicities but at the same time markedly weakens radiation induced antitumor 
immunity facilitating disease relapse. In addition, previous data have consistently shown that 
neoadjuvant chemoradiotherapy results in a decrease in the number of tumor infiltrating 
lymphocytes (28). It is also known that higher number of tumor infiltrating lymphocytes have been 
shown to be a prognostic marker associated with decreased distant recurrence rate (29). 
Based on these data and the activity of durvalumab in esophageal cancer, we hypothesize that 
adjuvant PD-L1 inhibition following chemoradiotherapy and surgery in esophageal cancer patients 
who do not achieve a complete pathological response with trimodality therapy will decrease the risk 
of cancer recurrence and improve relapse free survival through simulation of the immune system to 
eradicate residual disease. This phase II trial aims to evaluate the safety and efficacy of durvalumab 
in patients with persistent esophageal cancer following chemoradiotherapy and surgical resection. 
  
1.2 Therapeutic Durvalumab (MEDI4736) Background 
MEDI4736 is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa (IgG1κ) 
subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], 
cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). 
MEDI4736 is composed of 2 identical heavy chains and 2 identical light chains, with an overall 


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molecular weight of approximately 149 kDa. MEDI4736 contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein 
C1q and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
 
1.2.1 Summary of Non-clinical Experience: 
The non-clinical experience is fully described in the current version of the durvalumab 
(MEDI4736) Investigator’s Brochure (IB).    
 
MEDI4736 binds with high affinity and specificity to human PD-L1 and blocks its interaction with 
PD-1 and CD80. In vitro studies demonstrate that MEDI4736 antagonizes the inhibitory effect of 
PD-L1 on primary human T cells, resulting in their restored proliferation and release of interferon 
gamma (IFN-γ). Additionally, MEDI4736 demonstrated a lack of antibody-dependent cell-mediated 
cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based functional 
assays. In vivo studies show that MEDI4736 inhibits tumor growth in a xenograft model via a T 
lymphocyte (T-cell) dependent mechanism. Moreover, an anti-mouse PD-L1 antibody demonstrated 
improved survival in a syngeneic tumor model when given as monotherapy and resulted in complete 
tumor regression in > 50% of treated mice when given in combination with chemotherapy. 
Combination therapy (dual targeting of PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 
[CTLA-4]) resulted in tumor regression in a mouse model of colorectal cancer.  
Cynomolgus monkeys were selected as the only relevant species for evaluation of the 
pharmacokinetics (PK)/pharmacodynamics and potential toxicity of MEDI4736. Following 
intravenous (IV) administration, the PK of MEDI4736 in cynomolgus monkeys was nonlinear. 
Systemic clearance (CL) decreased and concentration half-life (t1/2) increased with increasing 
doses, suggesting saturable target binding-mediated clearance of MEDI4736. No apparent gender 
differences in PK profiles were observed for MEDI4736.  
In general, treatment of cynomolgus monkeys with MEDI4736 was not associated with any 
MEDI4736-related adverse effects that were considered to be of relevance to humans. Adverse 
findings in the non-Good Laboratory Practice (GLP) PK/pharmacodynamics and dose range-finding 
study, and a GLP 4-week repeat-dose toxicity study were consistent with antidrug antibody (ADA)-
associated morbidity and mortality in individual animals. The death of a single animal in the non-
GLP, PK/pharmacodynamics, and dose range-finding study was consistent with an ADA-associated 
acute anaphylactic reaction. The spectrum of findings, especially the clinical signs and microscopic 
pathology, in a single animal in the GLP, 4-week, repeat-dose study was also consistent with ADA 
immune complex deposition, and ADA:MEDI4736 immune complexes were identified in a 
subsequent non-GLP, investigative immunohistochemistry study. Similar observations were 
reported in cynomolgus monkeys administered human mAbs unrelated to MEDI4736. Given that 
immunogenicity of human mAbs in nonclinical species is generally not predictive of responses in 
humans, the ADA-associated morbidity and mortality were not considered for the determination of 
the no-observed-adverse-effect level (NOAEL) of MEDI4736.  
Finally, data from the pivotal 3-month GLP toxicity study with MEDI4736 in cynomolgus monkeys 
showed that subchronic dosing of MEDI4736 was not associated with any adverse effects. 
Therefore, the NOAEL of MEDI4736 in all the general toxicity studies was considered to be 100 
mg/kg, the highest dose tested in these studies. In addition to the in vivo toxicology data, no 
unexpected membrane binding of MEDI4736 to human or cynomolgus monkey tissues was 


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observed in GLP tissue cross-reactivity studies using normal human and cynomolgus monkey 
tissues. 
1.2.2 Summary of Clinical Experience: 
Clinical experience with durvalumab (MEDI4736) is fully described in the current version of the 
durvalumab (MEDI4736) Investigator’s Brochure. 
 
As of the data cutoff dates (15Apr2015 to 12Jul2015), a total of 1,883 subjects have been enrolled 
and treated in 30 ongoing MEDI4736 clinical studies, including 20 sponsored and 10 collaborative 
studies. Of the 1,883 subjects, 1,279 received MEDI4736 monotherapy, 440 received MEDI4736 
in combination with tremelimumab or other anticancer agents, 14 received other agents (1 
gefitinib, 13 MEDI6383), and 150 have been treated with blinded investigational product. No 
studies have been completed or terminated prematurely due to toxicity. 
 
1.2.3 Pharmacokinetics and Product Metabolism  
MEDI4736 monotherapy exhibited nonlinear (dose-dependent) PK. The area under the 
concentration-time curve from 0 to 14 days (AUC0-14) increased in a greater than dose-proportional 
manner over the dose range of 0.1 to 15 mg/kg and approached linearity at ≥ 3 mg/kg, suggesting 
that the nonlinear PK of MEDI4736 is likely due to saturable target-mediated clearance. Exposures 
following multiple doses (currently up to a maximum of 26 doses) demonstrated accumulation 
consistent with PK parameters estimated from the first dose. Suppression of free soluble PD-L1 
(sPD-L1) was correlated with MEDI4736 PK concentrations. Following administration of 
MEDI4736 monotherapy, free sPD-L1 levels were below the lower limit of quantitation (LLOQ) in 
the majority of subjects with available data (n = 38) at all timepoints following IV doses ≥ 1 mg/kg 
every 2 weeks (Q2W).   
 
Overall, a low incidence of ADA was observed. Of the 220 subjects who received MEDI4736 
monotherapy and for whom PK/ADA data were available, 5 were detected ADA positive, with an 
impact on PK/pharmacodynamics reported in 1 subject.  
 
1.2.4 Safety:  
The safety profile of MEDI4736 as monotherapy and combined with other anticancer agents was 
consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-mediated AEs 
(imAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
MEDI4736 and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular 
toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an important 
potential risk particularly with MEDI4736 and tremelimumab combination therapy. These events 
are manageable by available/established treatment guidelines as described in the study protocols. 
 
AEs reported with MEDI4736 monotherapy and MEDI4736 and tremelimumab combination 
therapy in key clinical studies are described below. 
 
1.2.4.1 Adverse Event Profile of Durvalumab (MEDI4736) Monotherapy 
Study CD-ON-MEDI4736-1108: The safety profile of MEDI4736 monotherapy in the 694 subjects 
with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108 has been 
broadly consistent with that of the overall 1,279 subjects who have received MEDI4736 
monotherapy (not including subjects treated with blinded investigational product) across the clinical 


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development program. The majority of treatment-related AEs were manageable with dose delays, 
symptomatic treatment, and in the case of events suspected to have an immune basis, the use of 
established treatment guidelines for immune-mediated toxicity. As of 07May2015, among the 694 
subjects treated with MEDI4736 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108, a total of 378 
subjects (54.5%) experienced a treatment-related AE, with the most frequent (occurring in ≥ 5% of 
subjects) being fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus 
(6.3%), rash (6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were Grade 1 or 
Grade 2 in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment-related ≥ 
Grade 3 events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased 
aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase (GGT; 
6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and colitis, 
vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had treatment-
related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, neutropenia, 
colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related Grade 5 event (pneumonia). 
Treatment-related serious adverse events (SAEs) that occurred in ≥ 2 subjects were colitis and 
pneumonitis (3 subjects each). A majority of the treatment-related SAEs were ≥ Grade 3 in severity 
and resolved with or without sequelae. AEs that resulted in permanent discontinuation of MEDI4736 
were considered as treatment related in 18 subjects (2.6%), with colitis being the most frequent 
treatment-related AE resulting in discontinuation (3 subjects). A majority of the treatment-related 
AEs resulting in discontinuation of MEDI4736 were ≥ Grade 3 in severity and resolved with or 
without sequelae. 
 
Study D4191C00003/ATLANTIC: The safety profile of MEDI4736 monotherapy in Study CD-
ON-MEDI4736-1108 is generally consistent with that of Study D4191C00003/ATLANTIC in 
subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with 
MEDI4736 10 mg/kg Q2W. As of 05May2015, 264 of 303 subjects (87.1%) reported any AE in 
Study D4191C00003/ATLANTIC. Overall, events reported in ≥ 10% of subjects were dyspnea 
(18.8%), fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia (12.2%), asthenia 
(11.9%), and nausea (11.2%). Nearly two-thirds of the subjects experienced AEs that were Grade 1 
or 2 in severity and manageable by general treatment guidelines as described in the current 
MEDI4736 study protocols. Grade 3 or higher AEs were reported in 107 of 303 subjects (35.3%). 
A total of 128 subjects (42.2%) reported AEs that were considered by the investigator as related to 
investigational product. Treatment-related AEs (all grades) reported in ≥ 2% of subjects were 
decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); 
diarrhea, hyperthyroidism, hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased 
(2.3%); and vomiting (2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects were 
pneumonitis (3 subjects) and increased GGT (2 subjects). There was no treatment-related Grade 4 
or 5 AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of 
subjects were dyspnea (6.6%); pleural effusion, general physical health deterioration (2.3% each); 
pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, respiratory 
failure, disease progression (1.0% each). Nine subjects had an SAE considered by the investigator 
as related to MEDI4736. Each treatment-related SAE occurred in 1 subject each with the exception 
of pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have died due to an 
AE (pneumonia [3 subjects]; general physical health deterioration, disease progression, hemoptysis, 
dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, cardiopulmonary arrest [verbatim 
term (VT)], hepatic failure, and sepsis [1 subject each]). None of these events was considered related 
to MEDI4736. Twenty-three of 303 subjects (7.6%) permanently discontinued MEDI4736 treatment 


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due to AEs. Events that led to discontinuation of MEDI4736 in ≥ 2 subjects were dyspnea, general 
physical health deterioration, and pneumonia. Treatment-related AEs that led to discontinuation 
were increased ALT and increased hepatic enzyme, which occurred in 1 subject each. 
 
1.2.5 Efficacy:  
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies. 
 
Study CD-ON-MEDI4736-1108: Overall, 456 of 694 subjects treated with MEDI4736 10 mg/kg 
Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, measurable disease at 
baseline, and ≥ 1 follow-up scan, or discontinued due to disease progression or death without any 
follow-up scan). In PD-L1 unselected patients, the objective response rate (ORR), based on 
investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged 
from 0% in uveal melanoma (n = 23) to 20.0% in bladder cancer (n = 15), and disease control rate 
at 24 weeks (DCR-24w) ranged from 4.2% in triple-negative breast cancer (TNBC; n = 24) to 
39.1% in advanced cutaneous melanoma (n = 23). PD-L1 status was known for 383 of the 456 
response evaluable subjects. Across the PD-L1-positive tumors, ORR was highest for bladder 
cancer, advanced cutaneous melanoma, hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), 
NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the head and neck (SCCHN; n = 22, 
18.2%). In the PD-L1-positive subset, DCR-24w was highest in advanced cutaneous melanoma (n 
= 3, 66.7%), NSCLC (n = 86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and 
SCCHN (n = 22, 18.2%). 
 
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in Study 
D4190C00007, 21 subjects had at least 1 post-baseline disease assessment. Among these subjects, 
the best overall responses were marrow complete remission (mCR) in 4 subjects (19.0%); stable 
disease (SD) in 4 subjects (19.0%); and progressive disease (PD) in 5 subjects (23.8%). The 
remaining 8 subjects (38.1%) did not meet the criteria for complete remission (CR), mCR, partial 
remission (PR), SD, or PD at the date of assessment. 
 
Study CD-ON-MEDI4736-1161: Of the 65 subjects with metastatic or unresectable melanoma 
treated with the combination of MEDI4736 and BRAF inhibitor (BRAFi; dabrafenib)/MEK 
inhibitor (MEKi; trametinib), 63 subjects were evaluable for response. A total of 35 subjects 
(55.6%) had a best overall response of confirmed or unconfirmed PR. The disease control rate 
(DCR; CR + PR [regardless of confirmation] + SD ≥ 12 weeks) was 79.4%. 
 
Study D4190C00006: Of the 102 subjects with advanced NSCLC treated with MEDI4736 in 
combination with tremelimumab in Study D4190C00006, 63 subjects with at least 16 weeks of 
follow-up were evaluable for response (defined as measurable disease at baseline and at least 1 
follow-up scan; this included discontinuations due to disease progression or death without follow-
up scan). Of the 63 evaluable subjects, 17 (27%) had a best overall response of PR, 14 (22%) had 
SD, 22 (35%) had PD, and 10 (16%) were not evaluable. The ORR (confirmed and unconfirmed 
CR or PR) was 27% and the DCR (CR, PR, or SD) was 49% as assessed by RECIST v1.1. 
 


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1.3 Durvalumab (MEDI4736) Fixed Dosing 
A population PK model was developed for MEDI4736 using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of MEDI4736 
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of MEDI4736 was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was selected 
to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were 
simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body 
WT-based and fixed dosing regimens yield similar median steady state PK concentrations with 
slightly less overall between-subject variability with fixed dosing regimen.   
 
Similar findings have been reported by others. Wang and colleagues investigated 12 monoclonal 
antibodies and found that fixed and body size-based dosing perform similarly, with fixed dosing 
being better for 7 of 12 antibodies. In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-subject variability in pharmacokinetic/pharmacodynamics parameters. (30) 
 
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, AstraZeneca 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 1500 mg Q4W MEDI4736 (equivalent to 20 mg/kg Q4W) is included in the current 
study. Fixed dosing of durvalumab is recommend only for subjects with > 30kg body weight due 
to endotoxin exposure.  Patients with a body weight less than or equal to 30 kg should be dosed 
using a weight-based dosing schedule.  
 
2. OBJECTIVES, ENDPOINTS AND OUTCOME MEASURES 
 
2.1.Objectives 
2.1.1. 
Primary Objective:  
 To determine if postoperative adjuvant therapy with durvalumab improves 1 year 
relapse free survival (RFS) compared to historical rates in patients with persistent 
esophageal cancer following neoadjuvant chemoradiotherapy and esophagectomy. 
 
2.1.2. 
Secondary Objectives 
 To assess the toxicity and tolerability of durvalumab following trimodality therapy 
in patients with esophageal cancer. 
 
2.1.3. 
Correlative/ Exploratory Objectives 
 To assess changes in PD-L1 expression with chemoradiotherapy in esophageal 
cancer.  
 To analyze possible predictive biomarkers of 1 year RFS including PD-L1 
expression (at diagnosis and in residual disease) in tumor cells and tumor 
infiltrating lymphocytes (by histology and gene expression analysis – by pathway 
analysis and CIBERSORT), both within the tumor and in surrounding connective 
tissue. 


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 To assess the Immunoscore (based on numeration of lymphocyte populations - 
CD3/CD45RO, CD3/CD8, CD8/CD45RO) – within the center and invasive 
margins of the tumor – and correlate it with 1 year RFS. 
 To analyze the correlation between changes in circulating tumor cell numbers in 
response to PD-L1 inhibition and 1 year RFS in patients with residual esophageal 
cancer. 
 
2.2.Endpoints 
2.2.1. 
Primary Endpoint 
1 year relapse free survival 
 
2.2.2. 
Secondary Endpoints 
Toxicity and tolerability of PD-L1 inhibition after trimodality therapy in patients 
with esophageal cancer. 
 
2.3.Outcome Measures 
2.3.1. 
Primary Outcome Measure 
Relapse free survival at 1 year. History and physical examination to be performed 
every 4 weeks while the patient is receiving durvalumab. CT scan of the chest and 
abdomen will be performed every 3 months to assess for disease recurrence.  
 
2.3.2. 
Secondary Outcome Measures 
Incidence and severity of adverse events related to the study drug – to be assessed 
at every visit, which will be every 4 weeks prior to the next dose of durvalumab. 
 
We will also collect data on regimen received (carboplatin/paclitaxel or cisplatin/5-FU), histology 
(adenocarcinoma), and amount and site of residual disease (primary tumor only or with lymph node 
involvement) for descriptive purposes. 
 
 
 


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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: 
 
3.1.1 Written informed consent and HIPAA authorization for release of protected health 
information obtained from the subject prior to performing any protocol-related procedures, 
including screening evaluations. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
3.1.2 Age ≥ 18 years at the time of consent. 
 
3.1.3 ECOG Performance Status of 0-1 within 28 days prior to registration for protocol therapy. 
 
3.1.4 Females of childbearing potential and males must be willing to use two effective methods 
of contraception (See section 5.5.1) from the time consent is signed until 3 months after 
treatment discontinuation. 
 
3.1.5 Females of childbearing potential must have a negative serum pregnancy test within 14 days 
prior to registration for protocol therapy. 
NOTE:  Female subjects are considered of childbearing potential unless they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are ≥60 years old and naturally postmenopausal for at least 12 
consecutive months. See section 5.5.1. 
 
3.1.6 Histological evidence of persistent residual esophageal adenocarcinoma including 
gastroesophageal junction adenocarcinoma following definitive concurrent 
chemoradiotherapy (carboplatin and paclitaxel or cisplatin and 5-FU) in the surgical sample 
(esophagus or lymph node or both) obtained at the time of esophagectomy.  
NOTE: Persistent residual disease is defined as follows (modified from College of 
American Pathologists Guidelines): 
- 
No residual tumor (Grade 0, complete response, 0% tumor). This group will not be 
included in this study. 
- 
Marked response (Grade 1, 0-<10% residual tumor) 
- 
Moderate response (Grade 2, 10-50% residual tumor) 
- 
No definite response (Grade 3, >50% residual tumor) 
 
3.1.7 Minimum of 1 month and maximum of 3 months from surgical resection with no evidence 
of disease progression at the time of enrollment. 
 
3.1.8 Must have adequately recovered from surgery as judged by the treating investigator. 
 
3.1.9 Laboratory values must be obtained within 28 days prior to registration for protocol 
therapy.   
 


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 White blood cell count (WBC) > 3 K/mm3 
 Hemoglobin (Hgb) > 9 g/dL. Transfusion is allowed, if needed, since patients are post 
esophagectomy.  
 Platelets >  100 K/mm3 
 Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
 Calculated creatinine clearance of > 40 cc/min using the Cockcroft-Gault formula or by 
24-hour urine collection for determination of creatinine clearance: 
 
 
Males:  (140 – Age in years) × Actual Body Weight in kg 
 72 × Serum Creatinine (mg/dL) 
 
Females:  Estimated creatinine clearance for males × 0.85 
 Bilirubin ≤ 1.5  ULN 
 Aspartate aminotransferase (AST, SGOT) < 2.5  ULN 
 Alanine aminotransferase (ALT, SGPT) < 2.5  ULN 
 
3.1.10 Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow up. 
 
3.2. Exclusion Criteria 
 
Subjects meeting any of the criteria below may not participate in the study: 
 
3.2.1 Prior therapy with a PD-1, PD-L1, or CTLA-4 inhibitor or cancer-specific vaccine therapy. 
 
3.2.2 Evidence of active autoimmune disease requiring systemic treatment within preceding 3 
months or a documented history of clinically severe autoimmune disease, or a syndrome 
that requires systemic steroids or immunosuppressive agents. Exceptions to this rule 
include vitiligo, resolved childhood asthma/atopy, requirement of intermittent 
bronchodilators or local steroid injections, hypothyroidism stable on hormone replacement, 
psoriasis not requiring systemic treatment (within the past 2 years), Graves’s disease and 
Sjogren’s syndrome. 
 
3.2.3 Prior malignancy is not allowed except for adequately treated basal cell or squamous cell 
skin cancer, in situ cervical cancer, Gleason score ≤ 7 prostate cancers, or other cancer for 
which the subject has been disease-free for at least 3 years. 
 
3.2.4 Active or prior documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative 
colitis). 
 
3.2.5 Presence of interstitial lung disease or history of pneumonitis requiring treatment with 
corticosteroids. 
 
3.2.6 Patients with diagnosis of primary immunodeficiency. 
 


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3.2.7 Patients receiving chronic systemic corticosteroid therapy or other immunosuppressive 
therapy within 28 days prior to registration for protocol therapy. Exceptions include 
intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, 
which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 
 
3.2.8 History of allogeneic organ or stem cell transplant. 
 
3.2.9 Receipt of live attenuated vaccine within 30 days prior to registration for protocol therapy. 
 
3.2.10 Mean QT interval corrected for heart rate (QTc) > 470 msec calculated from 3 ECGs by 
Bazett’s Correction. 
 
3.2.11 Ventricular arrhythmias requiring medication(s). 
 
3.2.12 Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, 
active peptic ulcer disease or gastritis, or active bleeding diatheses.  
 
3.2.13 History of psychiatric illness/social situations that would limit compliance with study 
requirements or compromise the ability of the subject to give written informed consent. 
 
3.2.14 Known HIV infection or chronic hepatitis B or C. 
 
3.2.15 Known history of previous clinical diagnosis of tuberculosis. 
 
3.2.16 Clinically significant infections as judged by the treating investigator. Clinically significant 
is defined as an active infection requiring IV antibiotics. 
 
3.2.17 Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother, breastfeeding should be discontinued.  In addition, 
breast milk cannot be stored for future use while the mother is being treated on study. 
 
3.2.18 Treatment with any investigational agent within 28 days prior to registration for protocol 
therapy.  
 
3.2.19 History of hypersensitivity to durvalumab or any excipient. 
 
3.2.20 Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
 
3.2.21 Previous enrollment in the present study. 
 
 
4. SUBJECT REGISTRATION  
All subjects must be registered and randomized through Big Ten CRC Administrative Headquarters’ 
electronic data capture (EDC) system. A subject is considered registered when an ‘On Study’ date 
is entered into the EDC system. 


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Subjects must be registered prior to starting protocol therapy. Subjects must begin therapy within 
five business days of registration.  
 
Blinding 
This study treatment is not blinded to the subject or the investigator. 
 
5. TREATMENT PLAN 
 
5.1.Pre-medication  
None 
 
5.2.Drug Administration 
 
Drug 
Dose 
Frequency of 
administration
Route of 
administration
Number of cycles 
Durvalumab 
1500 mg1 
Every 4 weeks 
(1 cycle) 
Intravenous 
Maximum 13 doses (12 
months), or until 
unacceptable toxicities or 
disease recurrence
1: Based on average body weight of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent 
to 20 mg/kg Q4W) is included in the current study. Fixed dosing of durvalumab is recommended 
only for subjects with > 30kg body weight due to endotoxin exposure.  Patients with a body weight 
less than or equal to 30 kg should be dosed using a weight-based dosing schedule. 
 
NOTE: Infusions may be given ±3 days for reasons such as observed holidays, inclement weather, 
scheduling conflicts, etc. It should be clearly documented in subject’s chart and case report forms. 
 
The body surface area and drug dose should be recalculated only if subject’s weight changes by       
≥ 10% during the course of the study. 
 
5.2.1. Missed doses:  
Missed doses can be made up within 8 days of the missed dose. 
 
5.3. Supportive Care:  
Institutional standards should be followed for hydration and transfusions. 
 
5.4. Concurrent Therapy 
None 
 
 


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5.5. Restrictions during the study 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapy 
2. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy 
for cancer treatment, other than any stated comparator or combination regimens. Concurrent 
use of hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable.   
3. Immunosuppressive medications including, but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-
α blockers. Use of immunosuppressive medications for the management of investigational 
product-related AEs or in subjects with contrast allergies is acceptable. In addition, use of 
inhaled and intranasal corticosteroids is permitted. A temporary period of steroids will be 
allowed for different indications, at the discretion of the principal investigator (e.g., chronic 
obstructive pulmonary disease, radiation, nausea, etc). 
4. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the first 
dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab.)  
Inactivated viruses, such as those in the influenza vaccine, are permitted. 
 
5.5.1.Contraception 
Females of childbearing potential who are sexually active with a nonsterilized male partner must 
use 2 methods of effective contraception from screening, and must agree to continue using such 
precautions for 3 months (90 days) after the final dose of investigational product, or for at least 90 
days following the last infusion of durvalumab; cessation of birth control after this point should be 
discussed with a responsible physician.  Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. 
 
 Female subjects are considered of childbearing potential unless they are surgically sterile (they 
have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are 
≥60 years old and naturally postmenopausal for at least 12 consecutive months. 
 Subjects must use 2 acceptable methods of effective contraception as described in the table 
below. 
 Nonsterilized males who are sexually active with a female partner of childbearing potential 
must use 2 acceptable methods of effective contraception (see Table 1 below) from Day 1 and 
for 90 days after receipt of the final dose of investigational product. 
 


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Table 1 
Effective methods of contraception (two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal 
Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Combined pill
Minipill 
Patch 
a 
This is also considered a hormonal method. 
 
5.5.2.Blood donation 
Subjects should not donate blood while participating in this study and for at least 90 days 
following the last infusion of durvalumab. 
 
 
6. DOSE MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 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 the Study Calendar and 
Evaluations section. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring protocol therapy interruption or discontinuation at each study visit for the duration of their 
participation in the study.   
 
Subjects discontinued from the treatment phase of the study for any reason will be evaluated at least 
30 days (+ 7) after the last dose of protocol therapy. 
 
 
6.1. Dose Modifications 
 
6.1.1. Dose Modifications and Toxicity Management for Durvalumab: 
 
For adverse events (AEs) that are considered at least partly due to administration of durvalumab the 
following dose adjustment guidance may be applied: 


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 Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
 If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab along with appropriate continuing supportive care.  If 
medically appropriate, dose modifications are permitted for durvalumab (see below). 
 All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued. 
 
Following the first dose of durvalumab, subsequent administration of durvalumab can be modified 
based on toxicities observed (see Tables 2, 3 and 4 below). Dose reductions are not permitted.  
 
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, there 
is the possibility of observing immune-mediated Adverse Events (imAEs) during the conduct of this 
study.  Potential imAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies. Subjects should be monitored for signs and symptoms of imAEs.  In the absence 
of an alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, dermatitis, 
hepatitis, and endocrinopathy should be considered to be immune-related.   
 
Dose modification recommendations and toxicity management guidelines for immune-mediated 
adverse events, for infusion-related reactions, and for non-immune-mediated adverse events are 
detailed in Tables 2, 3, and 4, respectively.   
 
In addition, management guidelines for adverse events of special interest (AESIs) are detailed in 
Section 10.1.3. All toxicities will be graded according to NCI CTCAE v4. 


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Table 2  Dosing Modifications and Toxicity Management Guidelines for Immune-Mediated, Infusion Related,  
and Non Immune-mediated Reactions for Durvalumab Monotherapy (1 November 2017 Version) 
General Considerations 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4. 
In addition to the criteria for permanent discontinuation of study drug/regimen based 
on CTC grade/severity (table below), permanently discontinue study drug/study 
regimen for the following conditions:  
 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose of study drug/regimen 
 
Recurrence of a previously experienced Grade 3 treatment-related AE following 
resumption of dosing. 
It is recommended that management of immune-mediated 
adverse events (imAEs) follow 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 (greater than 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 2-4 mg/kg/day PO or IV 
equivalent]) until stabilization or improvement of symptoms, 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until grade 2 resolution to ≤ Grade 1 
• 
If toxicity worsens then treat as Grade 3 or Grade 4 
• 
Study drug/study regimen can be resumed once event stabilizes to Grade 
≤1 after completion of steroid taper. 
• 
Patients with endocrinopathies who may require prolonged or continued 
steroid replacement can be retreated with study drug/study regimen on 
the following conditions: 
1. The event stabilizes and is controlled. 
2. The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. Doses of prednisone are at ≤10 mg/day or equivalent.
Grade 3 
• 
Depending on the individual toxicity, may permanently discontinue 
study drug/study regimen. Please refer to guidelines below 
Grade 4 
Permanently discontinue study drug/study regimen  
Note:  For Grade 3 and above asymptomatic amylase or lipase levels hold study 
drug/regimen and if complete work up shows no evidence of pancreatitis, may 
continue or resume study drug/regimen. 
 
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 


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Table 2  Dosing Modifications and Toxicity Management Guidelines for Immune-Mediated, Infusion Related,  
and Non Immune-mediated Reactions for Durvalumab Monotherapy (1 November 2017 Version) 
General Considerations 
Dose Modifications 
Toxicity Management 
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). 
then resume corticosteroid tapering at a slower rate 
(>28 days of taper). 
- More potent immunosuppressives such as TNF inhibitors 
(eg, infliximab) (also refer to individual sections of the 
immune-related adverse event 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 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 is not mandated for Grade 3 / 
Grade 4 inflammatory reactions attributed to local tumour 
response (e.g. inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study drug 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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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
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 modification required. 
However, consider holding study 
drug/study regimen dosing as clinically 
appropriate and during diagnostic work-
up for other etiologies. 
For Grade 1 (Radiographic Changes Only) 
- Monitor and closely follow up in 2-4 days for clinical 
symptoms, pulse oximetry (resting and exertion) and 
laboratory work-up and then as clinically indicated. 
- Consider pulmonary and infectious disease consult. 
Grade 2  
(Symptomatic, 
medical intervention 
indicated, limiting 
instrumental ADL)  
Hold study drug/study regimen dose 
until grade 2 resolution to ≤ Grade 1. 
• If toxicity worsens then treat as 
Grade 3 or Grade 4.  
• If toxicity improves to ≤ Grade 1 
then the decision to reinitiate study 
drug/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). 
- Reimaging as clinically indicated. 
- If no improvement within 3-5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
- If still no improvement within 3-5 days despite IV 
methylprednisolone at 2-4/g/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(infliximab at 5 mg/kg every 2 weeks). Caution: 
Important to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab.  
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungal or anti 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections (Category 2B 
recommendation)i 
- Consider pulmonary and infectious disease consult. 
- Consider, as necessary, discussing with study sponsor-
investigator via the Big Ten CRC project manager.
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 consult; consider, 
as necessary, discussing with sponsor investigator. 
- Hospitalize the patient 
- Supportive Care (eg, oxygen) 
- If no improvement within 3-5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors (eg, 
infliximab at 5mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab  
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and in 
particular, anti PJP treatment (please refer to current 
NCCN guidelines for treatment of cancer-related 
infections (Category 2B recommendation)i 
Diarrhea/ Colitis 
Any Grade 
General Guidance 
For Any Grade: 
- Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency over 
baseline or blood in stool) or related to bowel perforation 
(such as sepsis, peritoneal signs and ileus). 
- Patients should be thoroughly evaluated to rule out any 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
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. 
- Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis.
Grade 1 
(Diarrhea: stool 
frequency of <4 per 
day over baseline)  
(Colitis: 
asymptomatic; 
clinical or diagnostic 
observations only) 
No dose modifications. 
For Grade 1:  
- Close monitoring for worsening symptoms 
- Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical judgment. 
Grade 2  
(Diarrhea: stool 
frequency of 4-6 per 
day over baseline)  
(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 3-5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, GI consult should be obtained for 
consideration of further workup such as imaging and/or 
colonoscopy to confirm colitis and rule out perforation, 
and prompt treatment with IV methylprednisolone 2 to 4 
mg/kg/day started.  
- If still no improvement within 3-5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeksi. 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 sponsor-
investigator (via the Big Ten CRC project manager) if no 
resolution to ≤ Grade 1 in 3-4 days. 
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])i.
Grade 3 or 4 
 
(Grade 3 diarrhea: 
stool frequency of ≥7 
per day over 
baseline) 
 
(Grade 4 diarrhea: 
life threatening 
consequences) 
 
(Grade 3 colitis: 
severe abdominal 
pain, change in 
bowel habits, 
medical intervention 
indicated, peritoneal 
signs; 
Grade 4 colitis: life-
threatening 
Grade 3 
Permanently discontinue study 
drug/study regimen 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 3-5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, 
promptly start further immunosuppressives (eg infliximab 
at 5 mg/kg once every 2 weeks). Caution: Ensure GI 
consult to rule out bowel perforation and refer to 
infliximab label for general guidance before using 
infliximab.  
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti-
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])i. 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
consequences, urgent 
intervention 
indicated) 
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 total bilirubin (T bili) 
- Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications) 
Grade 1  
(AST or ALT > ULN 
and ≤ to 3 × ULN 
and/or T bili > ULN < 
1.5 × ULN) 
No dose modification 
If it worsens, treat as Grade 2 event 
For Grade 1 
- Continue LFT monitoring per protocol   
Grade 2  
(AST or ALT > 3 to 
5 × ULN and/or T 
bili >1.5- 3.0 × ULN)
Hold Study drug/study regimen dose 
until grade 2 resolution to ≤ Grade 1 
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4. 
• 
If improves to ≤ Grade 1 or baseline 
then resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2:  
- Regular and frequent checking of LFTs (e.g. every 1-2 
days) until elevations of these are improving or resolved.   
- If no resolution to ≤ Grade 1 in 1-2 days, consider, as 
necessary, discussing with sponsor-investigator (via the 
Big Ten CRC project manager). 
- If event is persistent (> 3-5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.  
- If still no improvement within 3-5 days despite 1 to 2 
mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
- If still no improvement within 3-5 days despite 2 to 4 
mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil)i. 
Discuss with sponsor-investigator (via the Big Ten CRC 
project manager) if mycophenolate mofetil is not available.  
PLEASE SEE 
shaded area 
immediately 
below this section 
to find guidance 
for management 
of “Hepatitis 
(elevated LFTS)” 
in HCC patients 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
Infliximab should NOT be used. 
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])i. 
Grade 3 or 4 
(Grade 3: AST or 
ALT >5-20 × ULN 
and/or T bili > 3.0-10 
× ULN) 
 
Grade 4  
(AST or ALT > 20 × 
ULN and/or T bili > 
10 × ULN) 
  
For Grade 3: 
For elevations in transaminases ≤ 8 × 
ULN, or elevations in bilirubin ≤ 5 × 
ULN:  
- -Hold study drug/study regimen 
dose until resolution to ≤ Grade 1 or 
baseline   
- -Resume study drug/study regimen 
if elevations downgrade ≤ Grade 1 
or baseline within 14 days and after 
completion of steroid taper 
- Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to ≤ Grade 1 or 
baseline within 14 days  
For elevations in transaminases > 8 × 
ULN or elevations in bilirubin > 5 × 
ULN, discontinue study drug/study 
regimen.  
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST and /or 
ALT > 3× ULN + bilirubin > 2× ULN 
without initial findings of cholestasis 
For Grade 3 or 4: 
- Promptly initiate empiric IV methylprednisolone at 1 to 4 
mg/kg/day or equivalent.  
- If still no improvement within 3-5 days despite 1 to 4 
mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil).  Discuss with study sponsor-
investigator (via the Big Ten CRC project manager) if 
mycophenolate is not available. Infliximab should NOT 
be used. 
- Hepatology consult, abdominal workup, and imaging as 
appropriate. 
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])i. 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
(i.e. elevated alkaline phos) and in the 
absence of any alternative causeii
For Grade 4:  
Permanently discontinue study 
drug/study regimen.  
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 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, 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 
THIS shaded 
area is guidance 
only for 
management of 
“Hepatitis 
(elevated LFTs)” 
in HCC patients  


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
 
Grade 1 
(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 
Grade 2 event. 
For all grades, 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
 
 
Grade 2 
(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 Grade 2 resolution to Grade ≤1 
or baseline. 
 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
- 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. 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
 
Grade 3 
(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 Grade ≤1 or 
baseline 
 
Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper. 
 
Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria, in the 
absence of any alternative cause.b 
For Grade 3: 
- 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 [Category 2B 
recommendation]).i 
 
Grade 4 
(Isolated AST or 
ALT >20×ULN,  
whether normal or 
elevated at baseline) 
 
 
Permanently discontinue study 
drug/study regimen. 
For Grade 4: 
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 Grade 1 transaminase rise as instructed for Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine)  
Any Grade  
General Guidance 
For Any Grade: 
- Consult with Nephrologist 
- Monitor for signs and symptoms that may be related to 
changes in renal function (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.
Grade 1 
(Serum Creatinine > 
1-1.5× baseline; > 
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 it worsens, depending on the severity, treat as Grade 
2 or Grade 3 or 4.  
- Consider symptomatic treatment including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
(Serum 
Creatinine>1.5-3.0× 
baseline; >1.5-
3.0×ULN) 
 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline. 
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to ≤ Grade 1 or 
baseline then resume study 
For Grade 2:  
- Consider symptomatic treatment including hydration, 
electrolyte replacement, and diuretics.  
- Carefully monitor serum creatinine every 2-3 days and as 
clinically warranted. 
- Consult Nephrologist and consider renal biopsy if 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
drug/study regimen after completion 
of steroid taper. 
clinically indicated. 
- If event is persistent (> 3-5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.  
- If event is not responsive within 3-5 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 improving gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])i.  
- When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol.
Grade 3 or 4  
(Grade 3:  serum 
creatinine > 3.0 × 
baseline; >3.0-6.0 × 
ULN; 
 
Grade 4: serum 
creatinine > 6.0 × 
ULN)  
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4: 
- Carefully monitor serum creatinine on daily basis. 
- Consult Nephrologist and consider renal biopsy if 
clinically indicated. 
- Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.  
- If event is not responsive within 3-5 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 improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current  NCCN guidelines 
for treatment of  cancer-related infections [Category 2B 
recommendation])i


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
Rash 
(excluding 
Bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE 
v 4 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 SPONSOR-INVESTIGATOR SHOULD BE 
CONTACTED AND STUDY DRUG 
DISCONTINUED**
Grade 1  
No dose modification 
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- 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 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 3-5 
days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid. Consider, as 
necessary, discussing with sponsor-investigator (via the 
Big Ten CRC project manager) and promptly start 
systemic steroids prednisone 1 to 2 mg/kg/day or IV 
equivalent.   
- Consider skin biopsy if persistent for >1-2 weeks or 
recurs.


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
 
For Grade 3: 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
≤ Grade 1 or baseline within 30 days, 
then permanently discontinue Study 
drug/study regimen.  
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
- Consult dermatology  
- Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent.  
- Consider hospitalization. 
- Monitor extent of rash [Rule of Nines]. 
- Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])i 
- Consider, as necessary, discussing with study sponsor-
investigator (via the Big Ten CRC project manager). 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
and adrenal 
insufficiency 
Type 1 diabetes 
mellitus, 
hypophysitis, 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section) 
Any Grade  
(depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE v4 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
- Consider consulting an endocrinologist for endocrine 
events. 
- Consider, as necessary, discussing with study sponsor-
investigator (via the Big Ten CRC project manager). 
- Monitor patients for signs and symptoms of 
endocrinopathies.  Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, 
hypotension polydipsia, polyuria 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).


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
- For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as 
there are no other signs or symptoms of pancreatic 
inflammation.  
- If a patient experiences an AE that is thought to be 
possibly of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, 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 
endocrinology consult.
Grade 2  
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until subject 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.
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. 
- Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids. 
- Isolated Type 1 diabetes mellitus (DM) may be treated 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
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. 
 
with appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
- For all patients with abnormal endocrine work up, except 
for those with isolated hypothyroidism, or Type I DM, and 
as guided by endocrinologist, consider short-term, 
corticosteroids (e.g., 1-2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g. hydrocortisone, or sex 
hormones). 
- 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 
(please refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation])i 
- For patients with normal endocrine work up (lab or MRI 
scans), repeat labs/MRI as clinically indicated.
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 
Resume study drug/study regimen 
administration 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:
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). 
- Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids 
- Isolated Type 1 diabetes mellitus may be treated with 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
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. 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
- For adrenal crisis, severe dehydration, hypotension, or 
shock: immediately initiate intravenous corticosteroids 
with mineralocorticoid activity. 
- 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 
(please refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation])i
Neurotoxicity 
(includes but not 
limited to limbic 
encephalitis. 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre) 
Any Grade  
 
(Please refer to 
CTCAE v 4 for 
definition of 
severity/grade 
depending on type of 
neurotoxicity) 
General Guidance 
- 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). 
- Symptomatic treatment with neurological consult as 
appropriate. 
Grade 1 
No dose modifications 
For Grade 1: 
- See “Any Grade” recommendations above. 
Grade 2 
 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to ≤ 
Grade 1 
 
For sensory neuropathy/neuropathic 
pain, consider holding study 
drug/study regimen dose until 
resolution to ≤ Grade 1. 
o If toxicity worsens then treat as 
- Consider, as necessary, discussing with the study sponsor-
investigator (via the Big Ten CRC project manager). 
- 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 3-5 days despite 1 to 2 
mg/kg/day prednisone PO or IV equivalent, consider 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
Grade 3 or Grade 4  
 
Study drug/study regimen can be 
resumed once event improves to 
Grade ≤1 and after completion of 
steroid taper.
additional workup and promptly treat with additional 
immunosuppressive therapy (e.g. IVIgG).  
 
 
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 sponsor-
investigator (via the Big Ten CRC project manager). 
- Obtain neurology consult. 
- Consider hospitalization. 
- Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent.  
- If no improvement within 3-5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (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 
which can result in substantial morbidity or in the worst 
case, death. Special care should be taken for certain 
sentinel symptoms which may predict a more severe 
outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory 
insufficiency or autonomic instability. 
- 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 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of prompt 
and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult 
- Neurophysiologic diagnostic testing (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 IVIG.
Grade 1 
No dose modification 
For Grade 1: 
- Consider, as necessary, discussing with the study sponsor-
investigator (via the Big Ten CRC project manager). 
- Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
- Obtain a neurology consult 
Grade 2 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1. 
Permanently discontinue study 
drug/study regimen if it does not resolve 
to ≤ Grade 1 within 30 days or if there 
are signs of respiratory insufficiency or 
autonomic instability. 
 
Grade 2  
- Consider, as necessary, discussing with the study sponsor-
investigator (via the Big Ten CRC project manager).  
- Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
- Obtain a neurology consult.  
- Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS 
o Steroids may be successfully used to treat Myasthenia 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
Gravis. Important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist. 
o Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IVIG. Such 
decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient. 
o If Myasthenia Gravis-like neurotoxicity is present, 
consider starting acetylcholine esterase (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 
IVIG and followed by plasmapheresis if not responsive 
to IVIG.


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
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 or if there are signs of respiratory 
insufficiency or autonomic instability. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4 (severe or life threatening events):  
- Consider, as necessary, discussing with study sponsor-
investigator (via the Big Ten CRC project manager). 
- Recommend hospitalization. 
- Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS 
o Steroids may be successfully used to treat Myasthenia 
Gravis.  It should typically be administered in a monitored 
setting under supervision of a consulting neurologist. 
o Patients unable to tolerate steroids may be candidates for 
treatment with plasmapharesis or IVIG. 
o If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (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 IVIG 
and followed by plasmapheresis if not responsive to IVIG. 
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 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
(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) 
 
Grade 1 
(asymptomatic with 
laboratory (e.g., 
BNP) or cardiac 
imaging 
abnormalities) 
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 mild to 
moderate activity or 
exertion 
 
Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention 
 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.
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 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
Adverse Event 
Event Grade 
(CTCAE v. 4) 
Dose Modifications 
Toxicity Management 
indicated 
 
Grade 4: Life-
threatening 
consequences; urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support) 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
(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 [Category 2B 
recommendation]).i 
i: ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Pestow MD. 
ii: FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
 


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Table 4.  Dosing Modification and Toxicity Management Guidelines for Infusion-Related Reactions for Durvalumab Monotherapy  
(1 November 2017 Version) 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
- Management 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 Grade 2: 
- Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator.  
- Consider premedication per institutional standard prior to subsequent 
doses. 
- 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). 
 
 
 


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Table 5.  Dose Modification and Toxicity Management Guidelines for Non-Immune Mediated Reactions for Durvalumab 
Monotherapy (1 November 2017 Version) 
CTC Grade/ 
Severity 
Dose Modification 
Toxicity Management 
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be related to study 
treatment (i.e. events due to underlying disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly as per 
institutional standard 
1 
No dose adjustment 
Treat accordingly as per 
institutional standard 
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline. 
Treat accordingly as per 
institutional standard 
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline. 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 
14 days, resume study drug/study regimen administration at next scheduled dose. Otherwise, 
discontinue study drug/study regimen. 
Treat accordingly as per 
institutional standard 
4 
Discontinue Study drug/study regimen (Note: for Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and as per treating Investigator’s clinical 
judgment and in consultation with the sponsor-investigator.). 
Treat accordingly as per 
institutional standard 
 
Abbreviations: 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; 
imAE = immune-mediated adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PO = by 
mouth; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal. 
 


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7. STUDY CALENDAR & EVALUATIONS 
Study Day
Screen 
Cycle 1 
Cycle = 28 days 
Cycles 2-13 
30 Days Post 
Treatment
Follow up 
-28 days 
Day 1 (-3) 
Day 1 (±3) 
30 days (+7) 
after last dose
Every 3 months 
(±7 days)
REQUIRED ASSESSMENTS 
Informed Consent 
X
Diagnosis and Staging1 
X
Medical history 
X
Physical exam and ECOG PS 
X
X
X
X
X
Vital Signs2 
X
X (x5)
X (x3)
X
ECG3 
X (x3)
pre, post: C1D1 
pre, post: C4D1
X
LABORATORY TESTS 
Complete Blood Cell Count (CBC) with diff5
X
X4
X
X
Comprehensive Metabolic Profile (CMP), including GGT, 
LDH, magnesium, uric acid6 
X 
X4 
X 
X 
 
Amylase, lipase6 
X
X4
X
Urinalysis7 
X
X4
X
X
TSH. If TSH abnormal, check free T3, free T4.8
X
every even cycle 
Prothrombin Time, aPTT, INR9 
X
Calculated creatinine clearance 
X
Serum pregnancy (WOCP)10 
-14 days
AEs, imAEs, AESIs & concomitant meds 
X
X
X
DISEASE ASSESSMENT5 
CT chest, abdomen/pelvis 
X
Q 3 months11
Q 3 months11
TREATMENT EXPOSURE 
Durvalumab 
X
X
CORRELATIVE STUDIES 
CTC blood sample12 (Indiana University ONLY)- optional
Pre-dose 
pre-dose C4D1
At recurrence
Archived tissue samples13- mandatory 
X
Whole blood sample14- mandatory 
Pre-dose 
BANKING STUDIES 
Whole Blood15– optional 
X
Unstained Slides (diagnosis and surgery) 16- optional
X
Serum and Plasma17- optional 
X
X
FOLLOW-UP 
Survival 
X


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Footnotes: 
1: Diagnosis and Staging to include pathology report and TNM staging 
2: Vital signs to include temperature, blood pressure, pulse rate, respiratory rate, weight, and height (screen only). 
3: ECGs are required during screening, pre and post treatment on C1D1, pre and post treatment at C4D1, end of treatment, and at any other time point when 
clinically indicated. 
4: Cycle 1 Day 1 labs do not need to be repeated if done within 7 days prior to Day 1. 
5: CBC with diff and platelets to include: hemoglobin, platelet count, red blood cell count, total white cell count. 
6: CMP to include: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, calcium, chloride, 
creatinine, gamma glutamyl transferase (GGT), glucose, lactate dehydrogenase (LDH), magnesium, potassium, sodium, total bilirubin, total protein, urea or 
blood urea nitrogen (depending on local practice), uric acid. If total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome), fractionate into direct and 
indirect bilirubin. GGT at baseline and as clinically indicated. Amylase and lipase will be checked at screening; amylase and/or lipase (depending on local 
practice) will be checked prior to Day 1 of each cycle. 
7: Urinalysis performed at Screening, Day 1 of every cycle, and as clinically indicated. Urinalysis to include: bilirubin, blood, glucose, ketones, pH, protein, 
and specific gravity. Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red blood cells. 
8: Free T3 and free T4 will only be measured if screening TSH is abnormal. Free T3 and free T4 should also be measured if there is clinical suspicion of an 
adverse event related to the endocrine system. 
9: Prothrombin time, aPTT and INR only performed at Screening and as clinically indicated. 
10: Pregnancy test: Within 14 days of registration. 
11: Disease assessment will be performed every 3 months ±7 days (prior to Cycle 4, 7, 10, etc.). During follow up, disease assessment will be performed every 
3 months (±7 days) for up to 1 year from the time of treatment discontinuation (if they have not withdrawn consent). 
12: OPTIONAL - CTC blood samples will be collected at pre-dose Cycle 1 Day 1, pre-dose Cycle 4 Day 1 (3 months), and at the time of disease recurrence 
during treatment or follow up.  Please note that CTC blood samples will only be collected on consenting subjects enrolled at the Indiana University Melvin and 
Bren Simon Cancer Center. 
13: Submission of unstained slides from the subject’s archived initial diagnostic tumor tissue and tissue from the time of surgery is mandatory (if available).  
See the Correlative Laboratory Manual (CLM) for collection, processing, labeling, and shipping instructions. 
14: Mandatory submission of whole blood for gene expression analysis is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, 
labeling, and shipping instructions. 
15: Optional whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, labeling, and shipping 
instructions. 
16: Optional unstained slides for banking from archived FFPE tumor blocks from the time of diagnosis and the time of surgery are requested (if available). See 
CLM for collection, labeling, and shipping instructions. 
17: Optional serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30 Day Post Treatment visit. See CLM for collection, 
labeling, processing, and shipping instructions.


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7.1. Screening 
 
7.1.1. Within 28 days prior to registration for protocol therapy:  
 Screen for the eligibility for the trial. Patient must satisfy all the inclusion criteria and 
must not have any exclusion criterion. 
 Informed consent 
 Diagnosis and staging: pathology report and TNM staging. 
 Medical history 
 Physical exam and ECOG PS 
 Vital signs: temperature, blood pressure, pulse rate, respiratory rate, weight, and height 
(screen only). 
 12-lead ECG (in triplicate, 2-5 minutes apart). All 12-lead ECGs should be obtained 
after the subject has been resting in a supine position for at least 5 minutes in each 
case. 
 Complete blood count with differential (CBC): to include hemoglobin, platelet count, 
red blood cell count, total white cell count. 
 Comprehensive metabolic panel (CMP): to include albumin, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, bicarbonate, calcium, chloride, 
creatinine, gamma glutamyl transferase (GGT), glucose, lactate dehydrogenase, 
magnesium, potassium, sodium, total bilirubin, total protein, urea or blood urea 
nitrogen (depending on local practice), uric acid. If total bilirubin is ≥2xULN (and no 
evidence of Gilbert’s syndrome), fractionate into direct and indirect bilirubin. GGT at 
baseline and as clinically indicated. 
 Amylase and lipase 
 Urinalysis: to include bilirubin, blood, glucose, ketones, pH, protein, and specific 
gravity. Microscopy should be used as appropriate to investigate white blood cells and 
use the high power field for red blood cells. 
 Thyroid stimulating hormone. Free T3 and free T4 will only be measured if TSH is 
abnormal. 
 Prothrombin time, aPTT and INR 
 Calculated creatinine clearance using the Cockcroft-Gault formula or by 24-hour urine 
collection for determination of creatinine clearance. 
 [Within 14 days of registration] Serum pregnancy test for women of childbearing 
potential (WOCP) 
 Baseline signs and symptoms; concomitant medications.  
 Baseline CT scan of chest, abdomen and pelvis 
 
7.2. On Treatment 
 
7.2.1. Cycle 1 Day 1 (or within 3 days prior): 
 Physical exam and ECOG PS, weight 
 Vital signs: blood pressure and pulse rate will be measured before, during and after the 
infusion at the following times (based on a 60-minute infusion): 
1. At the beginning of the infusion (at 0 minutes ± 5 minutes) 
2. at 30 minutes after the start of infusion (± 5 minutes),  
3. at the end of infusion (at 60 minutes ± 5 minutes) 


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4. at 30 minutes post-infusion (90 minutes from the start of the infusion ± 5 minutes) 
5. at 60 minutes post-infusion (120 minutes from the start of the infusion ± 5 minutes) 
o The 1-hour post-infusion observation period will apply to the first infusion only 
and then for subsequent infusions as clinically indicated. 
o If the infusion takes longer than 60 minutes, blood pressure and pulse 
measurements should follow the principles described here (e.g. every 30 minutes), 
or more frequently if clinically indicated.  
 ECG within an hour prior to start of infusion and at least one time point 0 to 3 hours 
after the infusion. ECGs recorded during the treatment phase will be single tracing. The 
same method of assessment should be used throughout the study. Twelve-lead ECGs 
will be obtained after the subject has been resting in a supine position for at least 5 
minutes in each case.  
 Complete blood count with differential (CBC) 
 Comprehensive metabolic panel (CMP) 
 Amylase and/or lipase (depending on local practice) 
 Urinalysis 
 Durvalumab administration 
 Correlative studies:  
o CTC blood sample – optional (pre-dose) (collected only on subjects enrolled at 
Indiana University) 
o Whole blood- optional 
o Archived tissue samples from diagnosis and surgery (mandatory, if available) 
 Banking studies: 
o Whole blood- optional 
o Unstained slides from archived tumor blocks from diagnosis and surgery - 
(optional, if available) 
o Serum and plasma- optional 
 
Notes: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting protocol 
therapy. 
See CLM for collection, processing, labeling and shipping instructions. 
 
7.2.2. Cycle 2+ Day 1 (±3 days): 
 Physical exam and ECOG PS, weight 
 Vital signs: blood pressure and pulse rate will be measured before, during and after the 
infusion at the following times (based on a 60-minute infusion): 
1. At the beginning of the infusion (at 0 minutes ± 5 minutes) 
2. at 30 minutes after the start of infusion (± 5 minutes),  
3. at the end of infusion (at 60 minutes ± 5 minutes) 
o If the infusion takes longer than 60 minutes, blood pressure and pulse 
measurements should follow the principles described here (e.g. every 30 minutes), 
or more frequently if clinically indicated. 
 Complete blood count with differential (CBC) 
 Comprehensive metabolic panel (CMP) 
 Amylase and/or lipase (depending on local practice) 


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 Urinalysis 
 Adverse events, immune-related adverse events, adverse events of special interest and 
concomitant medications 
 Durvalumab administration 
 Every 3 months (prior to Cycle 4, 7, 10, etc.): CT of chest, abdomen and pelvis 
 Cycle 4 Day 1: (in addition to procedures listed above) 
o ECG within an hour prior to start of infusion and at least one time point 0 to 3 
hours after the infusion. ECGs recorded during the treatment phase will be single 
tracing. The same method of assessment should be used throughout the study. 
Twelve-lead ECGs will be obtained after the subject has been resting in a supine 
position for at least 5 minutes in each case. 
o Pre-dose C4D1 Correlative studies:  
 CTC blood sample - optional (pre-dose) (collected only on subjects enrolled at 
Indiana University) 
 
7.3. Protocol therapy discontinuation 
A subject will be discontinued from the protocol therapy under the following circumstances: 
 Grade ≥ 3 infusion reaction 
 If there is clear evidence of disease relapse (per RECIST 1.1). NOTE: If pseudoprogression 
is suspected, a subject will be allowed to continue durvalumab until biopsy or repeat 
radiographic scans confirm disease relapse.  
 If the treating physician thinks a change of therapy would be in the best interest of the 
subject 
 If the subject requests to discontinue protocol therapy 
 If the protocol therapy exhibits unacceptable toxicity 
 If a female subject becomes pregnant  
 If protocol therapy is interrupted for ≥ 42 days due to a treatment-related adverse event.  
 
7.4. Safety Follow-up: 30 days (±7 days) after last dose of protocol therapy  
Subjects discontinued from the treatment phase of the study for any reason will be evaluated 30 
days (± 7) after the last dose of study drug or as soon as possible thereafter (ex. protocol therapy 
interruption for ≥ 42 days). If a subject is discontinued due to disease relapse, the subject will be 
off study after the Safety Follow-up visit and no further follow up will be performed. 
 Physical exam and ECOG PS 
 Vital signs: temperature, blood pressure, pulse rate, respiratory rate and weight 
 12-lead ECG. ECG should be obtained after the subject has been resting in a supine position 
for at least 5 minutes. The same method of assessment should be used throughout the study. 
 Complete blood count with differential (CBC) 
 Comprehensive metabolic panel (CMP) 
 Urinalysis 
 Adverse events, immune-related adverse events, adverse events of special interest and 
concomitant medications 
 Banking studies: 
o Serum and plasma- optional 
 


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7.5. At Recurrence:  
 Correlative studies:  
o CTC blood sample - optional (collected only on subjects enrolled at Indiana University) 
at the time of disease recurrence during treatment or follow up. 
 
7.6. Follow-up 
Subjects can stop study participation at any time. All subjects without documented disease relapse 
will be followed every 3 months for 1 year from the time of treatment discontinuation (if they have 
not withdrawn consent) for assessment of survival, disease relapse, and occurrence of any late AEs.  
 Physical exam and ECOG PS 
 CT scan of the chest and abdomen/ pelvis every 3 months for up to 1 year from the time of 
treatment discontinuation (if they have not withdrawn consent).  
 
Subjects will be off study after 1 year of follow-up from discontinuation of the study drug or at 
documented disease relapse, whichever comes first.  
 
 
8. CRITERIA FOR DISEASE EVALUATION 
 
In some circumstances it may be difficult to distinguish disease recurrence and relapse from 
inflammatory findings. It is recommended that a repeat disease assessment be performed if needed 
to confirm disease relapse prior to taking a subject off study. The disease assessment should be 
performed no sooner than 4 weeks after the criteria for relapse is first met. During this interim 
period, subjects should continue to be followed per protocol, including continued dosing of the 
study drug.  
 
8.1. Definitions for Disease Evaluation –RECIST version 1.1 [Eur J Ca 45:228-247, 2009] 
 
8.1.1. Disease Relapse:  
Any clinical or radiographic finding(s) that meet the criteria for measurable or non-
measurable lesions (confirmed by histology/cytology if solitary) according to RECIST 1.1. 
 If pseudoprogression is suspected, relapse will be confirmed by either a biopsy or 
repeat radiographic scans.  
 
8.1.2. Overall Survival: 
Overall Survival is defined by the date of registration to date of death from any cause. 
 
8.1.3. Relapse Free Survival: 
Time from the date of surgery until the criteria for disease relapse is met or death occurs.  
 
8.2. Methods of Measurement 
 
Both imaging-based evaluation and clinical examination will be used for assessment. The same 
imaging modality must be used throughout the study to measure disease. Baseline imaging should 
be available within 28 days of the first dose of study drug. 
 
8.2.1. CT and MRI: 


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CT and MRI are the best currently available and most reproducible imaging methods for assessing 
solid organ malignancy. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and the lesions should 
be measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST guidelines 
to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data, which may bias an investigator if it is not routinely or serially performed.   
 
8.2.2. Chest X-Ray: 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by an aerated lung (CT is preferable).   
 
8.2.3. Clinical Examination: 
Clinically detected lesions will only be considered measurable when they are superficial (e.g. skin 
nodules and palpable lymph nodes).  For skin lesions, documentation by color photography, 
including a ruler to estimate size of the lesion, is recommended.  Photographs should be retained at 
the institution. 
 
8.2.4. Cytology and Histology: 
Cytologic and histologic techniques can be used to confirm disease relapse (e.g. detection of an 
enlarged lymph node on imaging, to differentiate neoplastic from reactive etiology).  Cytologic 
confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is 
required if the effusion happens to be the sole suspected site of relapse. 
 
 
 


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9. BIOLOGICAL CORRELATIVES  
 
9.1 
Planned Correlative Studies: 
 Assessment of changes in PD-L1 expression with chemoradiotherapy in esophageal cancer and 
correlate with 1 year RFS. 
 Analysis of possible predictive biomarkers of 1 year RFS including PD-L1 expression (at 
diagnosis and in residual disease) and tumor infiltrating lymphocytes (by histology and gene 
expression analysis – by pathway analysis and CIBERSORT), both within the tumor and in 
surrounding connective tissue. 
 Assessment of the Immunoscore (based on numeration of lymphocyte populations - 
CD3/CD45RO, CD3/CD8, CD8/CD45RO – within the center and invasive margins of the tumor 
– and correlate it with 1 year RFS 
 Analysis of the correlation between changes in circulating tumor cell numbers in response to 
PD-L1 inhibition and 1 year RFS in patients with residual esophageal cancer 
 
9.2 
Source of Tissue Specimens for Correlative Studies:  
Specimens from the time of initial diagnosis (archived tissue) and the specimens obtained at the 
time of surgery (residual tumor and any positive lymph node) are mandatory (if available) for 
correlative studies. 
 
9.3 
PD-L1 expression using Tissue Microarrays (31) 
FFPE specimens obtained at the time of initial diagnosis as well as at the time of surgical 
resection.  
 
Automated QIF analysis using the AQUA method utilizing commercially available antibody.  
 
9.4 
Generation of Gene Expression Data 
 
9.4.1 Blood: 
Whole blood will be collected in standard BD Vacutainer EDTA tubes and frozen at -80C. Refer 
to the Correlative Laboratory Manual (CLM) for collection, processing, labeling, and shipping 
instructions. 
 
9.4.2 Tumor Specimens: 
Specimens from the time of initial diagnosis (archived tissue) and the specimens obtained at the 
time of surgery (residual tumor and any positive lymph node) will be submitted by sites to the 
Big Ten CRC biorepository.  Refer to the CLM for collection, processing, labeling, and shipping 
instructions. 
  
9.4.3 Sequencing Methods: 
For each sample, DNA & RNA will be extracted using the Qiagen All Prep Universal 
DNA/RNA/miRNA kit (Qiagen, Valencia CA). Briefly, 100ng of DNA will undergo a highly 
multiplexed PCR reaction to amplify all exons of 409 genes known to be mutated in cancer 
(Sanger Gene Census) using the Ion Ampliseq Comprehensive Cancer Panel. The Ion Ampliseq 
Comprehensive Cancer Panel is specifically designed for amplification of both formalin-fixed 
paraffin embedded samples as well fresh/frozen tissue. Subsequent to amplification, libraries 
will be sequenced on an Ion Proton Sequencer using 200bp fragment chemistry and an Ion 


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Proton I chip. An estimated 90 million reads per run will be generated. It is estimated that each 
sample will have 1500-2000X average coverage of each cancer gene, enabling low allele 
frequency somatic mutation detection. Each sequencing run will be evaluated for technical 
quality control metrics. For bioinformatics analysis, reads will be mapped to the human genome 
using the TMAP algorithm, which is integrated into the Ion Torrent Suite Software. After 
mapping, somatic variants will be called (point mutations, indels, and copy number variation), 
using the Ion Torrent Variant Caller (Life Technologies) and Ion Reporter (Life Technologies) 
software packages by identifying those mutations present in the tumor samples that are absent in 
the germline DNA derived from blood. Annotation of identified variants will be performed by 
cross-referencing the following databases: NIH dbSNP, 1000 genomes project, COSMIC 
(Catalog of Somatic Mutations in Cancer), and TCGA (The Cancer Genome Atlas). 
Identification of cancer driver variants, association with therapeutic interventions, and 
mutational network analyses will be performed using Ingenuity Variant Analysis (Ingenuity 
Systems). All data and analyses will be stored on the HIPPA-compliant Indiana University 
Scholarly Data Archive. 
 
For expression analysis, 10ng of RNA (extracted as described above) will undergo library 
preparation using the Ion Ampliseq Transcriptome Human Gene Expression Kit. This will allow 
for accurate quantitative expression of ~20,000 genes in the human genome. Standard workflow 
for gene-level expression will be conducted using Torrent Suite Version 5.0. The AmpliSeq 
Transcriptome Plugin tool will be used to generate standard expression files.   
 
9.5 
Tumor Infiltrating Lymphocytes 
Unstained slide of the specimen obtained at time of diagnosis and at the time of surgical resection 
including central area of the tumor and the invasive margin (32).  
 
9.6 
Immunoscore 
Two regular whole slide FFPE sections of the specimen obtained at time of diagnosis and at the 
time of surgical resection (33). 
 
9.7 
Optional Sample Banking for Future Studies 
Subject consent will be obtained for additional optional samples collected for future Big Ten 
Cancer Research Consortium studies. Hoosier Cancer Research Network, as Administrative 
Headquarters for the Big Ten CRC, will manage the banked samples. Samples will be banked 
indefinitely in the Hoosier Cancer Research Network Biorepository.  
This includes: 
 Whole blood:  
o Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma:  
o Whole blood for plasma will be collected prior to treatment on Cycle 1 Day 1 and at the 
30 Day Post Treatment Visit.  
 Pre- and Post-treatment serum:  
o Whole blood for serum will be collected prior to treatment on Cycle 1 Day 1 and at the 
30 Day Post Treatment Visit. 
 Unstained slides: (If Available) 
o Unstained slides will be obtained from the subject’s archived formalin fixed paraffin 
embedded tumor blocks from the time of diagnosis and from the surgical specimen.  


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Please refer to the CLM for all sample collection, processing, labeling, and shipping instructions. 
 
 
10. DRUG INFORMATION  
 
Please refer to the latest version of the IB, provided as a document separate from this protocol, for 
detailed information on toxicity associated with durvalumab. 
 
10.1. Drug Names:  
MEDI4736, durvalumab 
 
10.2. Drug Class: 
Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa (IgG1κ) 
subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], 
cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). 
 
10.3. Formulation, Packaging and Storage 
Durvalumab is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.  
 
The investigational product is supplied as a vialed liquid solution in clear 10R glass vials closed 
with an elastomeric stopper and a flip-off cap overseal. Each vial contains 500 mg (nominal) of 
active investigational product at a concentration of 50 mg/mL (500 mg/vial). The solution will be 
diluted with 0.9% (w/v) saline for IV infusion.  
 
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 secondary packaging until use to prevent excessive light exposure. 
Durvalumab must be used within the individually assigned expiry date on the label. 
 
In-use storage and stability 
Total in-use storage time from needle puncture of durvalumab vial to start of administration should 
not exceed 4 hours at room temperature or 24 hours at 2-8°C (36-46°F). If in-use storage time 
exceeds these limits, a new dose must be prepared from new vials. Infusion solutions must be 
allowed to equilibrate to room temperature prior to commencement of administration. Durvalumab 
does not contain preservatives and any unused portion must be discarded. 
 
10.4. Availability and Distribution 
AstraZeneca/MedImmune will supply durvalumab at no charge to subjects participating in this 
clinical trial. 
 
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. 
 


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10.5. Preparation  
The dose volume of durvalumab and number of vials needed for the subject to achieve the accurate 
dose will be calculated according to the durvalumab dose calculation worksheet found in the 
Documents/Info tab of the EDC. 
 
Preparation of infusion bags 
The preparation of infusion bags should be done under aseptic conditions by trained personnel; it 
should not be prepared on the ward. 
 
An additional volume of 0.9% (w/v) saline equal to the calculated volume of durvalumab to be 
added to the IV bag must be removed from the bag prior to addition of durvalumab.  
 
The calculated volume of durvalumab is then added to the IV bag, and the bag is mixed by gentle 
inversion to ensure homogeneity of the dose in the bag. 
 
Prior to the start of the infusion, ensure that the bag contents are at room temperature to avoid an 
infusion reaction due to the administration of the solution at low temperatures. 
 
Vials should be used for specific subjects and should not be shared between subjects. 
 
10.6. Administration 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion 
via an infusion pump into a peripheral vein. 
 
Following preparation of durvalumab, the entire contents of the IV bag should be administered as 
an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2-μm in-line filter.  
 
The IV line will be flushed with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered and document if the line was 
not flushed.  
 
Since the compatibility of durvalumab with other IV medications and solutions, other than normal 
saline (0.9% [weight/volume] sodium chloride for injection), is not known, the durvalumab solution 
should not be infused through an IV line in which other solutions or medications are being 
administered. 
 
10.7. Precautions 
Owing to the drug’s mechanism of action and nonclinical findings, subjects should be monitored 
for the development of immune-mediated adverse events such as enterocolitis, dermatitis, 
hepatitis/hepatotoxicity, endocrinopathy, pneumonitis, neuropathy, serious infection, infusion-
related reactions, anaphylaxis or serious allergic reaction, and immune complex disease.  
 
10.8. Side Effects 
For a comprehensive list of adverse events, please refer to the current version of the Investigator’s 
Brochure.  
 


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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.  
 
The identified risks with durvalumab monotherapy include the following: cough/productive 
cough, pneumonitis, ILD, dysphonia, ALT/AST increased, hepatitis, diarrhea, abdominal pain, 
colitis, hypothyroidism, hyperthyroidism, blood TSH increased, blood TSH decreased, adrenal 
insufficiency, hypophysitis/hypopituitarism, type 1 diabetes mellitus, diabetes insipidus, blood 
creatinine increased, dysuria, nephritis, rash, pruritus, night sweats, dermatitis myocarditis, 
pyrexia, peripheral edema, upper respiratory tract infections, pneumonia, oral candidiasis, dental 
and oral soft tissue infections, influenza, myalgia, myositis, polymyositis and infusion related 
reaction. 
 
The following events have been seen with other checkpoint inhibitors (Naidoo et al 2015, 
Champiat et al 2016) and/or may possibly occur due to the mechanism of action of the PD-1/PD-
L1 class or mAb therapeutics in general. 
 Potential imAEs including: 
o Pancreatitis  
o Other rare or less frequent events with a potential immune-mediated aetiology, eg, 
pericarditis, sarcoidosis, uveitis, and other events involving the eye (eg, keratitis and 
optic neuritis), skin (eg, scleroderma and vitiligo), and haematological (eg, haemolytic 
anaemia and immune thrombocytopenic purpura), rheumatological events 
(polymyalgia rheumatic and autoimmune arthritis), neuropathy/neuromuscular 
toxicities (eg, myasthenia gravis, Guillain Barre syndrome), vasculitis, non-infectious 
meningitis and non-infectious encephalitis. 
 Hypersensitivity reactions including: 
o Anaphylaxis and allergic reaction 
o Cytokine release syndrome 
o Immune complex disease 
 Other infections 
 
Please refer to the current version of the Investigator’s Brochure (IB) for additional information 
regarding this drug. 
 
11. ADVERSE EVENTS  
11.1. 
Definitions 
 
11.1.1. Adverse Event (AE): 
Any untoward medical occurrence in a subject or clinical trial participant which does not necessarily 
have a causal relationship with the treatment. An adverse event (AE) can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational 
product. 
 


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An AE includes but is not limited to any clinically significant worsening of a subject’s pre-existing 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or 
intervention by the investigator, or a finding judged by the investigator to represent a change beyond 
the range of normal physiologic fluctuation, should be reported as an AE. 
 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational 
product) or non-treatment-emergent. A non-treatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product.  
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
subject being enrolled into the study) for a documented pre-existing condition, that did not worsen 
from baseline, is not considered an AE (serious or non-serious). An untoward medical event 
occurring during the prescheduled elective procedure or routinely scheduled treatment should be 
recorded as an AE or SAE. 
 
11.1.2. Serious Adverse Event (SAE): 
A serious adverse event is any adverse event that: 
 
Results in death 
 
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 or prolongation of existing hospitalization 
 
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. 
 
11.1.3. Definition of Immune-Mediated Adverse Events (imAEs) 
Immune-related AEs are adverse events associated with the treatment of patients with 
immunotherapy treatments that appear to be associated with the immune therapy’s mechanism of 
action. Based on these potential imAEs, AstraZeneca/Medimmune has defined a list of specific 
adverse event terms (see AESIs below) that are selected adverse events that must be reported to 
Big Ten Cancer Research Consortium Administrative Headquarters (Big Ten CRC AHQ) 
within 24 hours from the time the site investigator is aware of such an occurrence, regardless of 
whether or not the site investigator considers the event to be related to study drug(s). See Section 
11.2 for reporting criteria. 
 
11.1.4. Definition of Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESIs) are events of scientific and medical interest specific to 
the further understanding of the durvalumab safety profile and require close monitoring and rapid 
communication by the investigator to the sponsor-investigator and Big Ten CRC AHQ. 


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Durvalumab AESIs may be serious or non-serious. The rapid reporting of these AESIs allows 
ongoing analysis of these events in order to characterize and understand them in association with 
the use of this investigational product. Adverse events that are both an SAE and an AESI should 
be reported one time as an SAE only. 
 
AESIs for durvalumab include: 
 
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 etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other 
events involving the eye/skin, hematological and rheumatological events, vasculitis, 
non-infectious meningitis and non-infectious encephalitis. 
 
11.1.4.1. Pneumonitis 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis has 
been reported with anti-PD-1 MAbs (Topalian et al, NEJM 2012). Initial work-up should include 
high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary consultation is 
highly recommended.  
 
Guidelines for the management of subjects with immune-mediated adverse events including 
pneumonitis are outlined in Section 6.1.1. 
 
11.1.4.2. Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-
L1 and anti-PD-1 therapy (Brahmer et al 2012). As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of MAbs can be caused by various 
mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid 
reactions against the MAb, and serum sickness. Acute allergic reactions may occur, may be 
severe, and may result in death. Acute allergic reactions may include hypotension, dyspnea, 
cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, arthralgia, 
bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting, 
and unresponsiveness. 
 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in Section 6.1.1. 
 


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11.1.4.3. Hepatic function abnormalities (hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies (Brahmer et al 2012). Inflammatory hepatitis has been reported in 3% to 9% of 
subjects treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab). The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, nausea, 
and/or mild fever and increased liver function tests such as AST, ALT, alkaline phosphatase, 
and/or total bilirubin. 
 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational product. 
Guidelines for management of subjects with hepatic function abnormality are outlined in Section 
6.1.1. 
 
Cases where a subject shows an AST or ALT ≥3×ULN or total bilirubin ≥ 2×ULN may need to 
be reported as SAEs, these cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. 
 
Criteria for Hy’s Law (FDA Guidance 2009) 
 The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo  
 Among 
trial 
subjects 
showing 
such 
aminotransferase 
elevations, 
often 
with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of serum 
total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)  
 No other reason can be found to explain the combination of increased aminotransferases and 
total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury. 
 
11.1.5. Unexpected Adverse Event: 
An adverse event not mentioned in the Investigator's Brochure or Prescribing Information or the 
specificity or severity of which is not consistent with the Investigator's Brochure or Prescribing 
Information, or is not included in the informed consent document as a potential risk. 
 
11.1.6. Related Adverse Event 
There is a reasonable possibility the drug caused the adverse experience. 
 
Unrelated 
The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event may be related to the investigational agent(s) 


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Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
11.2. 
Reporting 
 
11.2.1. Adverse Events (AEs) 
Adverse events (AEs) will be recorded from the time of consent and for at least 90 days after 
treatment discontinuation, regardless of whether or not the event(s) are considered related to trial 
medications. The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 will be utilized for AE reporting. A copy of the 
current CTCAE version can be downloaded from the CTEP website at http://ctep.cancer.gov.  
 
During the course of the study all AEs should be proactively followed up for each subject. The 
investigator is responsible for following all AEs until resolution, return to baseline status, or 
stabilization with the expectation that it will remain chronic, even if this extends beyond study drug 
administration. 
 
11.2.2. Serious Adverse Events (SAE)  
 
11.2.2.1. Site Requirements for Reporting SAEs: 
Investigators and other site personnel must report all SAEs occurring during the course of the 
study within one business day of discovery of the event. This includes events both related and 
unrelated to the investigational product or to the study procedure(s). The reporting period for 
SAEs is the period immediately following the time that written informed consent is obtained 
through 90 days after the last dose of durvalumab or until the initiation of alternative anticancer 
therapy.  
 
The completed SAE Submission Form (see Documents/Info tab of the EDC) must be sent 
electronically to SAFETY@hoosiercancer.org at Big Ten Cancer Research Consortium 
(Big Ten CRC) Administrative Headquarters (AHQ) within one business day of discovery 
of the event. The investigator is responsible for informing the IRB and/or the Regulatory 
Authority of the SAE as per local requirements. 
The original copy of the SAE Submission Form and the e-mail correspondence must be kept 
within the study file at the study site. 
Follow-up information must be sent electronically to Big Ten CRC AHQ at 
SAFETY@hoosiercancer.org, using a new SAE Submission Form stating that this is a follow-
up to the previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs.  
 
The follow-up information should describe:  
 whether the event has resolved or continues,  
 if and how it was treated,  
 whether the subject continued or withdrew from study participation. 
 


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11.2.3. Big Ten CRC AHQ Requirements for Reporting SAEs: 
 
11.2.3.1. Big Ten CRC AHQ Reporting to AstraZeneca/ MedImmune 
Big Ten CRC AHQ will submit all FDA reportable SAEs to AstraZeneca within one business 
day of receipt of the SAE Submission Form from the site. Big Ten CRC AHQ will submit a 
MedWatch Form to AstraZeneca and will provide follow-up information as reasonably 
requested. 
 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca, preferably using the MedDRA coding language for serious adverse 
events. This information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly. 
 
Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com 
 
11.2.3.2. Big Ten CRC AHQ Reporting to the Food and Drug Administration (FDA) 
Big Ten CRC AHQ will manage the Investigational New Drug Application (IND) associated 
with this protocol on behalf of Shadia Jalal, M.D., Sponsor-investigator. Big Ten CRC AHQ 
will cross-reference this submission according to local regulations to the AstraZeneca 
Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally, 
Big Ten CRC AHQ will submit a copy of these reports to AstraZeneca at the time of submission 
to FDA.  
 
Big Ten CRC AHQ will be responsible for all communication with the FDA including but not 
limited to 7 and 15 Day Reports, as well as an Annual Progress Report. Big Ten CRC AHQ will 
report to the FDA, regardless of the site of occurrence, any AE that is serious, unexpected, and 
reasonably related (i.e., possible, probably, definite) to the study treatment. The sponsor-
investigator will review these reports and determine if any revisions are needed to the protocol 
or consent. 
 
7-Day Reports: 
 Big Ten CRC AHQ will report unexpected fatal or life-threatening events associated with 
the use of the study treatment will be reported to the FDA. 
 Big Ten CRC AHQ will report these events either by fax or by phone as soon as possible 
but in no event later than 7 calendar days after the initial receipt of the information regarding 
the event. The fax should be sent to the FDA project manager assigned to the IND. A 
comprehensive written report will be submitted as an amendment to the IND within an 
additional 8 days (15 calendar days, total). 
15-Day Reports: 
 Big Ten CRC AHQ will submit all other serious unexpected events associated with the use 
of the study treatment to FDA as an amendment to the IND as soon as possible but in no 
event later than 15 calendar days after initial receipt of the information regarding the event.  
 
* A cover page should accompany the MedWatch form indicating the following: 
 “Notification from an Investigator Sponsored Study” 
 The investigator IND number assigned by the FDA 


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 The investigator’s name and address 
 The trial name/title and AstraZeneca ISS reference number (ESR-14-10654) 
 
* Sponsor must also indicate, either in the SAE report or in the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
 
Annual Progress Reports 
 Big Ten CRC AHQ will submit an annual progress report within 60 days of the anniversary 
of the date that the IND went into effect. 
 
11.2.4. Other events requiring immediate reporting 
 
11.2.4.1. Requirements for Reporting Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified 
in the Investigator’s Brochure, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is 
required to be reported to Big Ten CRC AHQ within 24 hours of knowledge of the event. Big 
Ten CRC AHQ will report the event to AstraZeneca/MedImmune Patient Safety or designee 
within 24 hours using the designated Safety e-mailbox. If the overdose results in an AE, the 
AE must also be recorded as an AE. Overdose does not automatically make an AE serious, but 
if the consequences of the overdose are serious, for example death or hospitalization, the event 
is serious and must be recorded and reported as an SAE. There is currently no specific 
treatment in the event of an overdose of durvalumab.  
 
The investigator will use clinical judgment to treat any overdose. 
 
11.2.4.2. Requirements for Reporting Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 11.1.4.3) in a study subject, with or 
without associated clinical manifestations, is required to be reported as “hepatic function 
abnormal” within 24 hours of knowledge of the event to Big Ten CRC AHQ, unless a 
definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct 
obstruction) that is unrelated to investigational product has been confirmed. Big Ten CRC 
AHQ will report the event to AstraZeneca/MedImmune Patient Safety or designee within 24 
hours using the designated Safety e-mailbox. 
 If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject 
will be based on the clinical judgment of the site investigator. 
 If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
 
Each reported event of hepatic function abnormality will be followed by the site investigator 
and evaluated by the sponsor-investigator and AstraZeneca/MedImmune.  
 


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11.2.4.3. Requirements for Reporting Pregnancy 
Pregnancy itself, or pregnancy of a subject’s partner, is not regarded as an adverse event unless 
there is a suspicion that the investigational product under study may have interfered with the 
effectiveness of a contraceptive medication. Congenital abnormalities/birth defects and 
spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of any conception occurring from 
the date of the first dose until 90 days after the last dose (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed 
up and documented even if the subject was withdrawn from the study drug.  
 
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to Big Ten CRC AHQ on the Pregnancy 
Report form (See Documents/Info tab of the EDC). Big Ten CRC AHQ will report the event 
to AstraZeneca/MedImmune Patient Safety or designee within 24 hours using the designated 
Safety e-mailbox. 
 
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to Big Ten CRC AHQ after outcome. Big Ten CRC AHQ will report the 
event to AstraZeneca/MedImmune Patient Safety or designee within 24 hours using the 
designated Safety e-mailbox. 
 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose.  
 
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to Big Ten CRC AHQ on the Pregnancy Report form (See 
Documents/Info tab of the EDC). The site investigator will endeavor to collect follow-up 
information on such pregnancies provided the partner of the study subject provides consent. 
 
11.3. 
IND Safety Reports Unrelated to This Trial 
IND safety reports not occurring on this trial but involving the study intervention (outside SAEs) 
received from outside sources will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines. The sponsor-investigator will review these reports 
and determine if any revisions are needed to the protocol or consent. 
 
 
12. STATISTICAL CONSIDERATIONS 
12.1. General Considerations 
Statistical analysis of this study will be the responsibility of Biostatistics and Data Management 
Core at Indiana University Melvin and Bren Simon Cancer Center (IUSCC). Parameter estimates 
and relevant summary statistics will be reported where appropriate. For continuous variables, 
summary statistics will include number of subjects, mean, median, standard deviation, minimum 
and maximum. Categorical endpoints will be summarized using number of subjects, frequency, and 
percentages. Missing data will not be imputed. Data analysis will be performed in SAS Version 9.4. 


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Additional exploratory analyses of the data will be conducted as deemed appropriate. Changes from 
this analysis plan will not require an amendment to the protocol unless it changes a significant 
feature of the protocol. 
 
12.2. Study Design 
This is an open label single-arm single-stage phase II trial.  
 
12.3. Definition of Primary Endpoint 
- 
Relapse free survival: Time from the date of surgery until the criteria for disease relapse 
is met or death occurs. 
- 
One year relapse free survival: Subject is alive and relapse free at one year post-surgery.   
 
12.4. Definitions of Secondary Endpoints 
- 
Toxicity and tolerability: The occurrence and rate of any AEs, SAEs, AESIs, or imAEs 
while being on study drug and up to 30 days of receiving the final dose of the study drug. 
 
12.5. Definitions of Correlative Endpoints 
- 
Programmed death ligand -1 expression at cellular level in the specimen of residual tissue 
obtained at the time of esophagectomy  
- 
Assessment of tumor infiltrating lymphocytes by histologic analysis within the tumor 
and in surrounding connective tissue 
- 
Immunoscore (based on numeration of lymphocyte populations – CD3/CD45RO, 
CD3/CD8, CD8/CD45RO) within the tumor and in surrounding connective tissue 
- 
Changes in the circulating tumor cells collected at baseline, at 3 months, and at the time 
of disease recurrence (during treatment or follow up). 
 
12.6. Sample Size/Accrual/Study Duration/Replacement Rules  
Historical outcomes of patients who receive chemoradiotherapy followed by surgical resection and 
are noted to have persistent disease at the time of surgery are poor with 50% of them recurring in 
the first year (34). We expect durvalumab to improve the relapse free survival at 1 year rate by 25%. 
The null hypothesis is that 1 year RFS with postoperative adjuvant durvalumab therapy in patients 
with persistent esophageal cancer following neoadjuvant chemoradiotherapy and esophagectomy is 
50% or less. Alternative hypothesis is that 1 year RFS with postoperative adjuvant durvalumab 
therapy in patients with persistent esophageal cancer following neoadjuvant chemoradiotherapy and 
esophagectomy is 75% or greater. With a maximum acceptable type I error (the probability of 
concluding that the drug is effective when it is actually not effective) of 0.05, and acceptable type 
II error (the probability of concluding that the drug is not effective when it is actually effective) of 
0.20, the calculated sample size is 23 evaluable patients. If the total number of patients free of relapse 
at 1 year is less than or equal to 15, the drug would not be considered for further study. Up to 26 
will be enrolled to allow for 10% unevaluable for efficacy. Subjects who receive less than 6 months 
of durvalumab for reasons unrelated to disease progression or toxicity will be replaced. Estimated 
accrual period is 18 months; follow up period of 12 months.  To improve accuracy for estimating 
the primary endpoint (1 year RFS) with a 95% confidence interval, an additional 11-16 patients 
beyond the initial planned 23 evaluable will be enrolled for a target of 39 enrolled and at least 34 
patients evaluable for 1 year RFS (to allow for approximately 10% unevaluable).  With n=34 


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evaluable, if the 1 year RFS is 75%, a 95% two-sided confidence interval will have a half-width of 
15% (using normal-approximation). 
 
12.7. Criteria for Stopping the Study 
Safety: The first six subjects treated with at least one dose of study drug will be observed for a 
minimum of 60 days. During the 6th subject’s 60-day observation period, further accrual will be 
halted to evaluate "unacceptable toxicities warranting early closure of the trial" defined as: 
1) Any definitive durvalumab-related death. A durvalumab-related death will be continuously 
monitored throughout the trial and the trial will be suspended for re-evaluation whenever such 
an event is confirmed. 
2) Any unexpected and previously unreported grade 4 toxicities definitely related to durvalumab. 
 
If such events are observed in one subject, the DSMB will discuss and provide recommendations to 
the sponsor-investigator. If such events are observed in two or more subjects, the trial will be 
suspended for re-evaluation. 
 
Pneumonitis of grade 3 and 4 will be continuously monitored. An overall rate of 20% or above 
would be considered unacceptable. If the probability of the grade 3/4 pneumonitis rate being less 
than 20% drops below 0.1, the trial will be suspended for re-evaluation. 
 
12.8. Analysis Datasets 
 
Population 
Definition 
Enrolled 
This will comprise all patients who meet the eligibility 
criteria and are registered onto the study.  
Efficacy Evaluable  
This will comprise all patients who receive at least one dose 
of trial drug and either undergo at least one post-baseline 
assessment or die before any evaluation.     
Safety 
This will comprise all patients that receive at least one dose 
of durvalumab 
 
12.9. Subject Characteristics and significant protocol violations 
Subject demographics and subject baseline clinical characteristics will be listed and summarized 
for all subjects enrolled, including age, gender, and race by phase. Counts, means, medians, 
standard deviation, minimum and maximum values will be presented. Significant protocol 
violations will be listed. 
 
12.10. Concomitant Medication 
Concomitant medication use will be tabulated. 
  
12.11. Disposition 
Subject disposition will be tabulated and will show the number of subjects enrolled, and the 
number of subjects completing the study. All reasons for discontinuation will be listed and 
summarized. 
 


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12.12. Analysis Plan for Primary Objectives/Aims 
In the efficacy evaluable population, our primary analysis will be to estimate RPS at 1 year with a 
95% confidence interval.   Kaplan-Meier curve will also be estimated for the relapse free survival 
curve.  
 
12.13. Analysis Plan for Secondary Objectives/Aims 
In the safety population, toxicity will be summarized by rates and 95% confidence intervals. 
Toxicity analysis will be carried out after 30 days following receipt of the final dose of the study 
drug by the last study patient. We will tabulate AEs, AESIs, and imAEs, both with and without 
considering drug attribution. 
 
12.14. Analysis Plan for Correlative/Exploratory Objectives 
In the efficacy evaluable population, change in PD-L1 expression from diagnosis to surgery will 
be assessed using a paired t-test or Wilcoxon signed-rank test as appropriate. 
 
Changes in PD-L1 expression, Immunoscore values, and changes in CTCs over time will be 
correlated with 1 year RFS using two-sample tests or Wilcoxon rank sum tests as appropriate.  We 
will also explore time to event analyses with RFS using log-rank tests. 
 
Differential gene expression will be performed in R using DESeq2. These files will be 
downloaded and uploaded to Partek Genomics Suite v6.6 for visualization. Pathway analysis will 
be performed using Ingenuity Pathway Analysis.  CIBERSORT analysis to identify the immune 
cell make up based on gene expression will also be performed. 
 
 
13. TRIAL MANAGEMENT 
13.1 Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with Indiana University Melvin and Bren Simon 
Cancer Center Institutional Data and Safety Monitoring Plan (DSMP) for High Risk Phase II 
Trials. 
 
Big Ten CRC AHQ facilitated oversight activities for High Risk Phase II Trials include: 
 Review and processing of all adverse events requiring expedited reporting as defined in the 
protocol 
 Notify participating sites of adverse events requiring expedited reporting  
 Provide trial accrual progress, safety information, and data summary reports to the sponsor- 
investigator, including a weekly update of aggregate AE data. For any increase in frequency 
of grade 3 or above adverse events (above the rate reported in the Investigator Brochure or 
package insert), the sponsor investigator will notify Big Ten CRC AHQ who will notify the 
DSMC Chair and Compliance Officer immediately. The notification will include the 
incidence of study adverse events, grades, and attributions, as well as investigator statements 
regarding comparison with risks per the IB/ package insert. 
 Coordinate monthly (Phase II) meetings which will include representation from each 
accruing site. 
o These meetings should include review of data, the number of subjects and significant 
toxicities as described in the protocol. Big Ten CRC AHQ should maintain meeting 
minutes and attendance for submission to the DSMC. 


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 Conduct the trial across all participating sites in accordance with the requirements set forth 
in the IUSCC DSMP. 
 
13.1.1 Big Ten CRC AHQ Study-Specific Data and Safety Monitoring Board (DSMB) 
This study will have a study-specific Data and Safety Monitoring Board (DSMB) managed 
through Big Ten CRC AHQ.  The Big Ten CRC AHQ DSMB will review and monitor study 
progress, toxicity, safety, and other data from this trial. The board is chaired by an independent 
medical oncologist or another qualified individual external to this trial.   
 
The DSMB will meet semi-annually during the active treatment and safety follow-up portion of 
the trial to review the following:  
 Monthly Summary Reports 
 Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary (including serious adverse events) 
o Study accrual patterns 
o Protocol deviations 
 Audit and/or monitoring results, if applicable 
 Data related to stopping rules described in study design 
 Big Ten CRC AHQ meeting minutes/ attendance 
 
After all information has been reviewed, the Big Ten CRC AHQ DSMB will provide a 
determination to the sponsor-investigator.  The report may indicate one or more of the 
following decisions: 
 Continuation of the trial without change 
 Continuation of trial with modifications as outlined by the board 
 Immediate suspension of trial for safety reasons with recommended plan of follow-up to 
minimize subject harm 
 Termination of trial 
 
Big Ten CRC AHQ will distribute the official DSMB determinations to the site investigators/ 
participating sites for submission to applicable oversight bodies, including their respective 
IRBs, according to the local policies and procedures.  
 
Documentation of DSMB outcomes will also be provided to MedImmune and the IUSCC DSMC 
Chair via the DSMC Compliance Auditor (see next section).   
 
Investigators will conduct continuous review of data and subject safety.  At any time during the 
conduct of the trial, if it is the opinion of the sponsor-investigator that the risks (or benefits) to the 
subject warrant early closure of the study, this decision should be made in writing to the IUSCC 
DSMC Chair and Compliance Officer. Alternatively, the IUSCC DSMC may initiate suspension 
or early closure of the study at any time based on its review of the DSMB study reports. 
 
13.1.2 IUSCC Data and Safety Monitoring Committee (DSMC) Oversight 
The IUSCC DSMC retains authority over this study and may request additional actions based on 
the study’s DSMB reports; however, the IUSCC DSMC defers to the study-specific DSMB for 
routine review and decision making per the IUSCC DSMP.   


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The IUSCC DSMC will review the study-specific DSMB reports semi-annually.  
 
When the study is due for DSMC review, the DSMC Compliance Auditor will request the most 
recent study summary reports, Big Ten CRC AHQ monthly meeting minutes, and DSMB 
Outcome Letter(s).  The DSMC Chair will administratively review these documents and may 
request additional reports. If no issues were found or if issues have been resolved, the DSMC 
Chair may accept the DSMB’s determination and allow the study to continue without doing a full 
DSMC review. For DSMB suspensions or other issues of concern, the DSMC Chair will review at 
the DSMC Monthly meeting and may refer to the DSMC Full Meeting as needed for further 
discussion.  
 
Trials managed by Big Ten CRC AHQ are not routinely audited or monitored by IUSCC; 
however, the IUSCC DSMC retains the right to audit Big Ten CRC trials on a for cause basis.  
 
IND Annual Reports  
For trials with an IND held locally by the IU principal investigator or university, the IND Annual 
Report will be prepared and submitted to the IUSCC Compliance Officer. This report will be 
reviewed by the DSMC at the time of FDA submission.  
 
13.2 Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.  
 
13.2.1 Data Monitoring 
Monitoring will be conducted in accordance with the IUSCC DSMP for High Risk Phase II Trials.  
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause visits may occur as necessary. Selected 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 Big Ten CRC AHQ or its designee. 
 
The trial sites may also be subject to quality assurance audit by MedImmune or its designee as well 
as inspection by appropriate regulatory agencies. 
 
13.3 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 Big Ten CRC AHQ for registering the trial and posting 
the results on clinicaltrials.gov. Information posted will allow subjects to identify potentially 


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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 Case Report Forms and Submission 
This study will utilize electronic case report forms (eCRFs) in an electronic data capture (eDC) 
system. The eDC system will be compliant with Good Clinical Practices and Federal Rules and 
Regulations, to include 21 CFR Part 11.  
 
Generally, clinical data will be electronically captured in the eDC and correlative results will be 
captured in the eDC 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, according to study-specific objectives. Please see 
guidelines in the Documents/Info tab of the EDC for further details.  
 
The completed dataset is housed at Big Ten CRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without written permission 
from the sponsor-investigator and Big Ten CRC AHQ. After the initial publication, the complete 
data set will be available to all Big Ten CRC institutions. 
 
14.2 Record Retention 
To enable evaluations and/or audits from Health Authorities/Big Ten CRC AHQ, the investigator 
agrees to keep records, including the identity of all participating 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. To comply with international regulations, the 
records should be retained by the investigator in compliance with regulations. 
 
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRFs will 
be generated for each site and transmitted to the site and the site monitor. Corrections will be made 
by the study site personnel. This will be done on an ongoing basis. 
 
14.3 Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subject 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 secure, password protected electronic systems. Paper 
files that contain personal information will be kept in locked and secure locations only accessible to 
the study team. Samples that are collected will be identified by a subject 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 study number. 
 
Subjects will be informed in writing that some organizations including the sponsor-investigator and 
his/her research associates, Big Ten CRC AHQ, MedImmune, IRB, or government agencies, like 


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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. 
 
14.4 Changes to the Protocol and Informed Consent 
Study procedures will not be changed without the mutual agreement of the sponsor-investigator, 
Big Ten CRC AHQ, and MedImmune. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of the study 
protocol (amended protocol) will be generated by Big Ten CRC AHQ and must be approved by the 
Sponsor-Investigator and MedImmune in addition to each site’s IRB, and if applicable, also the 
local regulatory authority. Local requirements must be followed. 
 
If a protocol amendment requires a change to the informed consent form sites must notify their local 
IRB. Approval of the revised informed consent form by the local IRB is required before the revised 
form is used.  
 
The local investigator is responsible for the distribution of amended documents to his or her IRB, 
and to the staff at his or her center. The distribution of these documents to the regulatory authority 
will be handled according to local practice. 
 
MedImmune’s willingness to supply study drug is predicated upon the review of the protocol. Big 
Ten CRC AHQ agrees to provide written notice to MedImmune of any modifications to the protocol 
or informed consent. 
 
15 ETHICS 
15.1 Ethics Review 
The final study protocol, including the final version of the informed consent form, must be approved 
or given a favorable opinion in writing by an IRB. The local investigator must submit written 
approval to the Big Ten CRC AHQ office before he or she can enroll any subject into the study.  
 
The local 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 at least annually, as local 
regulations require.  
 
Progress reports and notifications of serious adverse events will be provided to the IRB according 
to local regulations and guidelines. 
 
The investigator is also responsible for providing the IRB with reports of any serious adverse events 
from any other study conducted with the investigational product, according to local policies. 
MedImmune will provide this information to the sponsor-investigator. These reports will be 
reviewed by the sponsor-investigator and will be forwarded to participating sites every 2 weeks for 
submission to their Institutional Review Boards per their guidelines.  
 


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15.2 Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration 
of Helsinki, which are consistent with ICH Good Clinical Practice, and applicable federal (including 
21 CFR parts 56 & 50), state, or local laws. 
 
15.3 Informed Consent Process 
The 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 investigator must store the original, signed written informed consent 
form. A copy of the informed consent form must be given to the subject. 
 
 


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