Clinical trial NCT02891161
Conditions: Urothelial Cancer
Keywords: durvalumab MEDI4736 anti-PD-L1
Sponsor: Monika Joshi, MD
Start date: 2016-11-16; Completion date: 2022-04-27
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an open label, multi-institutional, single arm study of a phase Ib study, followed by a phase II study of durvalumab with radiation therapy (RT) in patients with urothelial cancer (UC). No randomization or blinding is involved.

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

The phase Ib study will evaluate the safety of combining durvalumab with RT followed by adjuvant durvalumab. The phase II study will estimate the Progression Free Survival (PFS) and Disease Control Rate (DCR) with durvalumab plus RT followed by single agent durvalumab for patients with UC of bladder.

PHASE Ib INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of up to 6 patients who will receive durvalumab 1500mg 2 doses Q4 weekly with RT to gross disease, 64.8 Gy, 36 fractions on weekdays over about 7 weeks. Durvalumab will be started on day 1; RT will be started on day 1 or 2.

Three patients will be enrolled initially. If 2 or more patients (out of 3) experience dose-limiting toxicity (DLT), the combined treatment will be considered unsafe. Otherwise, an additional 3 patients will be treated at the same dose. If 0 or 1 patient experience DLT, the dose of durvalumab will be deemed safe for phase 2 part of the study. If, however, 2 or more patients (out of 6) experience DLT, the combined treatment will be considered unsafe.

Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks (±7 days) for a total period of up to 12 months. Adjuvant durvalumab treatment will be started 3-4 weeks post completion of durvalumab and RT.

PHASE II INVESTIGATIONAL TREATMENT:

Subjects will receive durvalumab 1500mg 2 doses Q4 weekly with RT to gross disease, 64.8 Gy, 36 fractions on weekdays over about 7 weeks. Durvalumab will start on Day 1. RT to start on Day 1 or 2.

Post-concurrent durvalumab and RT, single agent durvalumab will be given1500mg every 4 weeks (±7 days) for a total period of up to 12 months. Adjuvant durvalumab monotherapy will be started 3-4 weeks post completion of durvalumab and RT.

Life expectancy of \>6 months per treating physician.

Adequate organ and marrow function as defined below:

1. Hemoglobin ≥ 9.0 g/dL
2. Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (\> 1500 per mm\^3)
3. Platelet count ≥ 100 x 10\^9/L (\>100,000 per mm\^3)
4. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
5. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN.
6. Serum creatinine CL\>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

Arms: arm 1: Subjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1. RT to start on Day 1 or 2. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT. arm 2: Subjects will receive durvalumab 1500mg Q4 weekly with RT to gross disease over 36 fractions. Durvalumab will start on Day 1. RT to start on Day 1 or 2.. Subjects will receive adjuvant durvalumab monotherapy Q4 week, up to 12 months. Adjuvant durvalumab monotherapy to start 4 weeks post completion of durvalumab and RT.
Interventions: intervention 1: durvalumab intervention 2: Radiation Therapy
Intervention descriptions: intervention 1: 1500 mg Q4 weekly intervention 2: 64.8 Gy, 36 daily fractions on weekdays over about 7 weeks

Protocol documents:
Prot_SAP_000.pdf: 
  
Clinical Study Protocol 
 
 
 
 
BTCRC-GU15-023 
 
Phase Ib/II Study of Concurrent Durvalumab And Radiation Therapy (DUART) Followed by 
Adjuvant Durvalumab in Patients with Urothelial Cancer (T2-4 N0-2 M0) of the Bladder:  
Big Ten Cancer Research Consortium BTCRC-GU15-023  
 
Sponsor-Investigator 
Monika Joshi, MD, MRCP 
Penn State Cancer Institute 
 
Radiation Oncology Lead 
Leonard Tuanquin, MD- Co-PI 
Penn State Cancer Institute 
 
Medical Oncology 
Joseph Drabick, MD, FACP 
Penn State Cancer Institute 
Mark Stein, MD 
Rutgers Cancer Institute of New Jersey 
Sheldon Holder, MD, PhD 
Penn State Cancer Institute 
 
 
 
Surgical Oncology 
Mathew Kaag, MD 
Suzanne Merrill, MD 
Penn State Cancer Institute 
 
Correlative Co-investigators 
David Degraff, PhD 
Hong Zheng, MD, PhD 
Joshua Warrick, MD 
Penn State Cancer Institute 
 
Statisticians 
Jason Liao, PhD 
Junjia Zhu, PhD 
Penn State Cancer Institute 
 
Trial Management Provided by  
BTCRC Administrative Headquarters at Hoosier Cancer Research Network, Inc. 
7676 Interactive Way, Suite 120 
Indianapolis, IN 46278 
 
Trial Supported by  
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca PLC 
ESR-15-11352  
 
Investigational New Drug (IND) Application Number: 
131781 
 
Initial Protocol Version Date: 02SEP2016 
 
Protocol Amendment Version Date:  
01FEB2017 
04JAN2018  
26MAR2019 
18MAY2020 (current) 
 


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PROTOCOL SIGNATURE PAGE 
 
Phase Ib/II Study of Concurrent Durvalumab And Radiation Therapy (DUART) Followed by 
Adjuvant Durvalumab in Patients with Urothelial Cancer (T2-4 N0-2 M0) of the Bladder:  
Big Ten Cancer Research Consortium BTCRC-GU15-023 
 
 
VERSION DATE:  18MAY2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the 
ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for 
good clinical practices, whichever provides the greater protection of the individual.  I will accept the 
monitor’s overseeing of the study.  I will promptly submit the protocol to applicable ethical review 
board(s). 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
 Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
 
 
PLASE EMAIL COMPLETED FORM TO BTCRC ADMINISTRATIVE HEADQUARTERS 
 
 
 


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SYNOPSIS 
TITLE 
Phase Ib/II Study of Concurrent Durvalumab And Radiation Therapy (DUART) 
Followed by Adjuvant Durvalumab in Patients with Urothelial Cancer (T2-4 
N0-2 M0) of the Bladder
SHORT TITLE 
Durvalumab and Radiation Therapy (DUART) 
PHASE  
Ib and II 
OBJECTIVES 
Primary Objectives:  
Phase Ib: 
 To assess the safety of combining durvalumab with RT.  
Phase II: 
 To estimate the progression free survival (PFS) rate at 1 year.  
 To estimate the disease control rate (DCR) (DCR=complete response [CR] 
+partial response [PR] +stable disease [SD]) to concurrent durvaRT followed 
by durvalumab. 
Secondary Objectives: 
Phase Ib: 
 To estimate the DCR post completion of concurrent durvaRT.  
 To correlate the expression of PD-L1 on immunohistochemistry at pre-
treatment (TURBT specimen if possible) and post- durvaRT treatment 
(cystoscopy-biopsy 2-3 weeks post durvaRT) with DCR 
Phase II: 
 To estimate the median progression free survival (PFS) time.  
 To estimate the rate of complete remission (CR) post durvaRT by modified 
RECIST 1.1. 
 Estimate the overall survival (OS) 
Exploratory Objectives: 
 To explore the correlation between the PD-1, PD-L1 and FOXP3 (T-regulatory 
cells) expression on immunohistochemistry pre-treatment (TURBT specimen) 
and post- durvaRT treatment (cystoscopy-biopsy 2-3 weeks post durvaRT) 
with DCR, PFS and OS 
 We will also explore if the combination of RT with durvalumab increases the 
PD-L1+ status in tumor specimen when compared to baseline. We will 
compare the expression of PD-L1 on immunohistochemistry at pre-treatment 
(TURBT specimen if possible) and post- durvaRT treatment (cystoscopy-
biopsy 2-3 weeks post durvaRT) 
 To explore the correlation of PD-1 expression on T cells from peripheral blood 
with clinical outcomes. Peripheral blood will be collected at pretreatment, post 
durvaRT, and post completion of treatment with adjuvant durvalumab. 
 To explore correlation of next generation sequencing (NGS) of tumors and 
blood at pretreatment and at post durvaRT with response rate for durvaRT 
+adjuvant durvalumab. As part of NGS, RNA-seq would be performed and 
and we would attempt to perform immunosubtyping based on expression data, 
as well as perform deconvolution analysis in an effort to understand changes in 
tumor immune cell inflammation. In addition, we will do next generation


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sequencing of urine cell free DNA at pretreatment and will correlate with 
tumor sequencing at pretreatment stage. * 
 To explore the correlation of plasma cytokines such as IFN-γ level with 
clinical outcomes. Peripheral blood will be collected prior to durvaRT, post 
completion of durvaRT and post treatment of adjuvant durvalumab. 
Inflammatory cytokines such as IFN-γ concentration in plasma will be 
assessed by Bead-based immunoassays. In addition, intracellular cytokine 
release by CD4 and CD8 T cells, and their phenotypic subsets, will be assessed 
by flow cytometry. Correlation between the level of cytokine production and 
clinical outcomes (RR, PFS, OS) will be analyzed.* 
 
* Contingent upon available funding.
STUDY DESIGN 
Single arm study to assess the safety of combining durvalumab with RT in phase 
Ib cohort followed by expansion to phase II cohort. The patients from Phase Ib 
will be rolled over and combined with patients in Phase II in the analysis.
KEY 
ELIGIBILITY 
CRITERIA  
Phase Ib subjects: 
 Locally advanced urothelial cancer of bladder who have any of the following: 
o T3-4, N0-2 M0, OR Tx N1-2 M0 OR T2 N1-2 M0 treatment naïve who are 
either unresectable, OR medically unfit for surgery* OR cisplatin 
ineligible**. Please note that T3 N0 M0 patients can be included if they are 
cisplatin ineligible**.  
o Patients who have T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-
neoadjuvant chemotherapy who become unresectable OR are medically 
unfit for surgery*  
Phase II subjects: 
 Locally advanced urothelial cancer of bladder with any of the following:  
o T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, 
unresectable, OR medically unfit for surgery* OR cisplatin ineligible**. 
Please note that T3 N0 M0 patients can be included if they are cisplatin 
ineligible**.  
o T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients post-
neoadjuvant chemotherapy who become unresectable OR unfit for surgery* 
(Please note: the stage of tumor is based on prechemotherapy status at the 
time of diagnosis) 
 T2, N0, M0 patients, treatment naïve, who are cisplatin ineligible** can be 
included in the study. 
 T2 N0 M0 patients who are treatment naïve or post neoadjuvant chemotherapy 
but are unfit for surgery* may also be enrolled.  
*Unfit for surgery is based on patient’s cardiac status or pulmonary status or any 
co-morbidity that can put patients at high risk for complications during or after 
surgery. “Unfit for surgery” status has to be determined by treating surgeon. 
**Cisplatin ineligiblity is defined by the presence of one or more of the 
following: 
 Impaired renal function (GFR ≥ 30 but ≤ 60 cc/min). GFR should be assessed 
by direct measurement (i.e. creatinine clearance or ethylenediaminetetra-


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acetate) or, if not available, by calculation from serum/plasma creatinine by 
Cockroft-Gault equation. 
 Grade ≥ 2 Hearing Loss (hearing loss measured by audiometry of 25 dB at 
two contiguous frequencies) 
 Grade ≥ 2 peripheral neuropathy  
 ECOG Performance Status of 2 
 Solitary Kidney 
 Any other medical condition that makes patient cisplatin ineligible based on 
assessment by treating Oncologist, such as severe coronary artery disease 
(CAD), congestive heart failure, etc.  
All subjects: 
 Written informed consent and HIPPA authorization obtained from the subject 
prior to performing any protocol-related procedures, including screening 
evaluations  
 Age > 18 years at time of informed consent 
 Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
 Life expectancy of >6 months per treating physician 
 Histologically proven pure or mixed urothelial carcinoma of bladder. Small 
cell histology would be excluded  
 Subjects must have archival tissue available from previous TURBT (preferred) 
or lymph node core biopsy within 8 weeks of treatment or be assessed by the 
treating urologist to undergo maximal TURBT. The extent of TURBT may 
vary for each patient and will be determined by the treating urologist. Further, 
the treating urologist will decide if performing the TURBT is clinically 
appropriate. If the potential subject does not have tumor amenable to biopsy, 
there is insufficient tissue for PD-L1 testing or is not clinically appropriate for 
TURBT, enrollment must be discussed with the sponsor-investigator on a 
case-by-case basis. 
 Adequate normal organ and marrow function as defined below:  
o Hemoglobin ≥ 9.0 g/dL 
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥ 1500 per mm3) 
o Platelet count ≥ 100 x 109/L (≥100,000 per mm3) 
o Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will 
not apply to subjects with confirmed Gilbert’s syndrome (persistent or 
recurrent hyperbilirubinemia that is predominantly unconjugated in the 
absence of hemolysis or hepatic pathology), who will be allowed only in 
consultation with their physician. 
o AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal 
o Serum creatinine CL>30 mL/min by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976) or by 24-hour urine collection for determination 
of creatinine clearance: 
Males: 
Creatinine CL (mL/min) 
=
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
 
Females: 


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Creatinine CL (mL/min) 
=
Weight (kg) x (140 – Age)        x 0.85 
72 x serum creatinine (mg/dL) 
 Female subjects must either be of non-reproductive potential (ie, post-
menopausal by history: ≥60 years old and no menses for 1 year without an 
alternative medical cause; OR history of hysterectomy, OR history of bilateral 
tubal ligation, OR history of bilateral oophorectomy) or must have a negative 
serum pregnancy test upon study entry.   
 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. 
 No previous systemic immunotherapy. Previous use of intravesical BCG is 
acceptable 
 No previous radiation therapy to the pelvic area.
STATISTICAL 
CONSIDERATIONS 
Statistical Methods and Data Analysis: 
Descriptive statistics will be used in the study to analyze patient’s characteristics 
and demographics. In particular, patient age, race, weight, ECOG performance 
status will be described. For phase Ib, the incidence and type of DLTs will be 
tabulated and reported at the dose level. Other toxicity information will be 
summarized via frequency tables by type and grade of toxicity. The combined 
treatment will be considered safe to continue to phase II part of the study if 0 or 
1 patient (out of 6) experiences DLT. 
For phase II, the primary endpoints are the progression free survival (PFS) status 
at 1 year, and the disease control status (CR+PR+SD) post completion of 
durvaRT followed by adjuvant durvalumab. The PFS will be analyzed using the 
Kaplan–Meier estimator with particular emphasis for one-year survival rate. 
Progression free survival rate at one year is defined as the probability that a 
patient remains free of progression of disease (SD+CR+PR) by modified 
RECIST 1.1 and cystoscopy at 1 year from the start of durvalumab treatment, 
D1 of durvaRT. The disease control status will be summarized using point 
estimate values of the relative frequency and their 95% confidence intervals. 
Appropriate statistical tests will be used to compare the PFS rate and the disease 
control rate from the study sample to the existing values from historical cohorts. 
The secondary endpoints include the progression-free survival (PFS) time, 
overall survival (OS) time, and the rate of complete remission (CR) post 
durvaRT by RECIST/cystoscopy. The survival (PFS and OS) time will be 
graphical displayed by the Kaplan-Meier survival curve. The median survival 
time and its 95% CI will be reported. The statistical methods use for analyzing 
the CR rate and relapse rate will be similar to that for the disease control rate. 
The bi-variate relationship between the outcome variables and some key some 
key clinical and demographic variables, such as tumor stage, ECOG status, 
smoking status, and gender, etc. will be examined by Fisher’s exact test or 
Kaplan-Meier test when appropriate. For the factors that show marginally 
significant relationship (for example, p<0.1), their relationship with the outcome 
variable will be reexamined by using some multiple regression methods, such as 
multiple logistic regression or multiple Cox proportional hazard regression. All 
analyses will be performed using statistical software SAS version 9.4 or higher 


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(SAS Institute, Cary, NC, USA). The statistical significance level to be used is 
0.05. 
Sample Size Determination: 
Statistical Power and Sample Size Considerations: The Phase Ib component 
consists of one dose level only so it requires a maximum of 6 patients. Given 
the safety is not dose dependent; no dose de-escalation will be allowed. For 
the Phase II component, we hope our therapy will increase the rate of PFS at 12 
months from 50% to 75%. There is paucity of literature to support the exact PFS 
rate for this subgroup of patients. As this study is expected to enroll higher stage 
patients with T4 or node positive disease, it is assumed that the historic PFS rate 
is around 50% at 1-year (PFS rate for stage IV patients who achieve CR is 
around 80% but those who do not achieve CR it falls between 0-40%). To reach 
a statistical power of at least 80% at one-sided alpha level of 5% and to allow 
for 10% drop out rate, a total of 26 patients are needed for this part which allows 
for 10% dropout. The second primary objective of Phase II is to estimate the 
disease control rate (DCR), which we assume to be about 75%. With 26 
combined patients in Phase Ib and Phase 2, we can, with 90% confidence, 
estimate DCR within 14% error. 
6 patients from the Phase Ib will be included in the analysis with patients from 
the Phase II portion for a  total number of patients of 26. 
TOTAL 
NUMBER OF 
SUBJECTS 
N = 26 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 36 months 
ESTIMATED 
STUDY 
DURATION  
Estimated 48 months 
 
 


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TABLE OF CONTENTS 
 
Synopsis ...................................................................................................................................................... 3 
Overall Study Schema ............................................................................................................................ 11 
Phase Ib Schema ...................................................................................................................................... 12 
Phase Ib Treatment Schema .................................................................................................................. 13 
Phase II Schema ...................................................................................................................................... 14 
Phase II Treatment Schema ................................................................................................................... 15 
Abbreviations and Definition of Terms ................................................................................................ 16 
1. 
Background and Rationale ................................................................................................................ 20 
1.1 
Disease Background.................................................................................................................. 20 
1.2 
Immunotherapy Treatment in UC ............................................................................................. 22 
1.3 
Durvalumab Treatment ............................................................................................................. 23 
1.4 
Rationale for combining durvalumab with RT ......................................................................... 28 
1.5 
Hypothesis: ............................................................................................................................... 29 
2. 
Study Objectives and Endpoints ....................................................................................................... 32 
2.1 
Objectives ................................................................................................................................. 32 
2.2 
Endpoints .................................................................................................................................. 33 
3. 
Eligibility Criteria ............................................................................................................................. 34 
3.1 
Inclusion Criteria ...................................................................................................................... 34 
3.2 
Exclusion Criteria ..................................................................................................................... 35 
4. 
Subject Registration .......................................................................................................................... 37 
5. 
Treatment Plan .................................................................................................................................. 39 
5.1 
Overview of Study Design ........................................................................................................ 39 
5.2 
Number of Subjects................................................................................................................... 39 
5.3 
Durvalumab Phase Ib Study...................................................................................................... 39 
5.4 
Durvalumab Phase II Study ...................................................................................................... 41 
5.5 
Radiation Therapy ..................................................................................................................... 42 
5.6 
Pre-medication and Hydration .................................................................................................. 45 
5.7 
Preparation of durvalumab doses for administration with an IV bag ....................................... 45 
5.8 
Durvalumab Administration ..................................................................................................... 45 
5.9 
Concomitant Medications ......................................................................................................... 46 
6. 
Toxicities and Dose Delays/Dose Modifications .............................................................................. 48 
6.1 
Dose Delays/Dose Modifications ............................................................................................. 48 
6.2 
Durvalumab............................................................................................................................... 49 
6.3 
Radiation Treatment Interruption ............................................................................................. 50 
6.4 
Toxicity management guidelines for combination treatment regimen ..................................... 51 
6.5 
Protocol Therapy Discontinuation ............................................................................................ 52 
7. 
Treatment Calendar & Evaluations ................................................................................................... 53 
Follow up Calendar & Evaluations ........................................................................................................... 54 
7.1 
Screening Evaluations ............................................................................................................... 57 
7.2 
On Treatment Evaluations ........................................................................................................ 58 
7.3 
Safety Follow-up Evaluations at End of Treatment .................................................................. 61 
7.4 
Long Term Follow-up Evaluations (±14 days) ......................................................................... 62 
7.5 
Description of study procedures ............................................................................................... 62 
8. 
Biospecimen Studies and Procedures ............................................................................................... 63 


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8.1 
Source and Timing of Biospecimen Collections ...................................................................... 63 
8.2 
PD-L1 Testing in tissue ............................................................................................................ 63 
8.3 
PD-1 expression on T cells from peripheral blood and IFN-γ in plasma ................................. 66 
8.4 
Urine cell free DNA (ucfDNA): ............................................................................................... 67 
8.5 
Next generation sequencing: ..................................................................................................... 67 
8.6 
Storage of Biospecimens........................................................................................................... 67 
8.7 
Banking of Leftover Biospecimens .......................................................................................... 68 
8.8 
Banking Samples for Future Unspecified Research ................................................................. 68 
8.9 
Confidentiality of Biospecimens ............................................................................................... 68 
9. 
Criteria for Disease Evaluation ......................................................................................................... 68 
9.1 
Safety and Efficacy variables .................................................................................................... 69 
9.2 
Measurable Disease .................................................................................................................. 70 
9.3 
Non-measurable Lesions ........................................................................................................... 71 
9.4 
Target Lesions ........................................................................................................................... 71 
9.5 
Non-target Lesions .................................................................................................................... 71 
9.6 
Evaluation of Target Lesions .................................................................................................... 71 
9.7 
Evaluation of Non-target Lesions ............................................................................................. 72 
9.8 
Evaluation of Best Overall Response ....................................................................................... 72 
9.9 
Definitions for Response Evaluation – RECIST 1.1 ................................................................ 74 
10. Drug Information .............................................................................................................................. 75 
10.1 
Durvalumab (MEDI4736) ......................................................................................................... 75 
10.2 
Supplier/How Supplied ............................................................................................................. 75 
10.3 
Preparation ................................................................................................................................ 75 
10.4 
Storage and Stability ................................................................................................................. 76 
10.5 
Administration .......................................................................................................................... 77 
10.6 
Precautions ................................................................................................................................ 77 
10.7 
Dispensing................................................................................................................................. 77 
10.8 
Adverse Events ......................................................................................................................... 77 
11. Adverse Events ................................................................................................................................. 78 
11.1 
Definitions................................................................................................................................. 78 
11.2 
Reporting................................................................................................................................... 83 
12. Statistical Methods ............................................................................................................................ 86 
12.1 
Study Design ............................................................................................................................. 86 
12.2 
Endpoints .................................................................................................................................. 87 
12.3 
Sample Size and Accrual .......................................................................................................... 87 
12.4 
Analysis Datasets ...................................................................................................................... 88 
12.5 
Assessment of Safety ................................................................................................................ 88 
12.6 
Assessment of Efficacy ............................................................................................................. 88 
12.7 
Data Analysis Plans .................................................................................................................. 89 
12.8 
Interim Analysis/Criteria for Stopping Study ........................................................................... 90 
13. Trial Management ............................................................................................................................. 90 
13.1 
Data and Safety Monitoring Plan (DSMP) ............................................................................... 90 
13.2 
Penn State Cancer Institute Data Safety Monitoring Board ..................................................... 91 
13.3 
Data Quality Oversight Activities ............................................................................................. 91 
13.4 
Compliance with Trial Registration and Results Posting Requirements .................................. 91 
14. Data Handling and Record Keeping ................................................................................................. 92 


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14.1 
Data Management ..................................................................................................................... 92 
14.2 
Case Report Forms and Submission ......................................................................................... 92 
14.3 
Record Retention ...................................................................................................................... 92 
14.4 
Confidentiality .......................................................................................................................... 92 
15. Ethics................................................................................................................................................. 93 
15.1 
Institutional Review Board (IRB) Approval ............................................................................. 93 
15.2 
Ethical Conduct of the Study .................................................................................................... 93 
15.3 
Informed Consent Process ........................................................................................................ 93 
Appendix 1 ................................................................................................................................................ 94 
Appendix 2 ................................................................................................................................................ 96 
Appendix 3 .............................................................................................................................................. 122 
Appendix 4 .............................................................................................................................................. 123 
Appendix 5 .............................................................................................................................................. 124 
16. References ....................................................................................................................................... 126 


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OVERALL STUDY SCHEMA 
N=26 patients  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with muscle invasive and locally advanced urothelial 
cancer of the bladder 
DurvaRT 
36 fractions of RT 
+ 
Q4 weeks durvalumab (2 doses) 
Adjuvant Durvalumab Monotherapy 
Q4 weeks durvalumab for up to 12 months 
Follow for progression and survival 
every 3 months for 3 years from the start 
of adjuvant treatment. 


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PHASE IB SCHEMA 
N=up to 6 patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with locally advanced urothelial bladder cancer 

T3-4 N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 treatment naïve patients who are unresectable or medically 
unfit for surgery OR cisplatin ineligible. T3 N0 M0 patients can be included if they are cisplatin ineligible.  

T3-4 N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-neoadjuvant chemotherapy who become unresectable 
OR are medically unfit for surgery 
CR, PR, SD
DurvaRT: 
Durvalumab 1500mg Q4 weeks (2 doses) 
with RT to gross disease, 36 fractions  
Durvalumab will start on Day 1 of RT 
Adjuvant durvalumab monotherapy: 
Durvalumab maintenance for pts with CR, PR, SD (Q4 weeks; up to 12 months) 
Durvalumab to start 4 weeks (±7) post completion of durvaRT 
Disease status by imaging and cystoscopy 2-3 weeks post 36 fractions of durvaRT. 
Subjects with confirmed PD per protocol will come off study treatment. 


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PHASE IB TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RT x 36 fractions  
Durvalumab: 
Q4 weeks (2 doses)  
Repeat cystoscopy 2-3 weeks post durvaRT, thereafter Q3 months 
Adjuvant durvalumab as monotherapy- Q4 weeks x 12 months (13 doses). 
To start 4 weeks after durvaRT. 
Eligibility and 
enrollment 


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PHASE II SCHEMA 
N=26 patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

T2, N0, M0 who are cisplatin ineligible 

T2 N0 M0 patients who are treatment naïve 
or post neoadjuvant chemotherapy but are 
unfit for surgery may also be enrolled. 
DurvaRT: 
Durvalumab 1500mg Q4 weeks (2 doses) 
 with RT -36 fractions 
Durvalumab to start on Day 1 
RT to start on Day 1 or 2
Adjuvant durvalumab monotherapy: 
Durvalumab maintenance for pts with CR, PR, SD 
 (Q4 weeks; up to 12 months). 
Durvalumab to start 4 weeks (±7) post completion of durvaRT  
Locally advanced Bladder Cancer 

T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2M0: 
Treatment naïve patients who are unresectable OR medically 
unfit for surgery OR cisplatin ineligible. T3 N0 M0 patients 
can be included if they are cisplatin ineligible.   

T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients 
post-neoadjuvant chemotherapy, who become unresectable 
OR medically unfit for surgery. (Stage of tumor is based on 
prechemotherapy status at the time of diagnosis) 
Disease status by imaging and cystoscopy 2-3 weeks 
post 36 fractions of durvaRT. 
Confirmed PD per protocol will come off study. 
CR, PR, SD


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PHASE II TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Durvalumab: 
Q4 weeks (2 doses) 
Repeat cystoscopy 2-3 weeks post durvaRT, thereafter Q3 months 
Adjuvant durvalumab as monotherapy- Q4 weeks x 12 months (13 doses). 
To start 4 weeks after durvaRT. 
RT x 36 fractions 
Eligibility and 
enrollment 


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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APC 
antigen-presenting cells 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
CDC 
Complement dependent cytotoxicity 
CI 
confidence interval 
CL 
clearance 
Cmax 
peak concentration 
Cmax,ss 
peak concentration at steady state 
Cmin 
trough concentration 
Cmin,ss 
trough concentration at steady state 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
CXCL 9 
The chemokine (C-X-C motif) ligand 9 
CXCL 10 
The chemokine (C-X-C motif) ligand 10 
CXCL 16 
The chemokine (C-X-C motif) ligand 16 
DC 
disease control 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
durvaRT 
Durvalumab+radiation 


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Abbreviation or 
special term 
Explanation 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
disodium edetate dihydrate 
Fc 
fragment crystallizable 
FDA                      
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
FSH 
follicle-stimulating hormone 
FTIH 
first-time-in-human 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HCl 
hydrochloride 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IGF 
insulin-like growth factor 
IgG1 
immunoglobulin G1 
IgG2 
immunoglobulin G2 
IGSF 
immunoglobulin superfamily 
IHC 
immunohistochemistry  
IL 
interleukin 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
MAb 
monoclonal antibody 
MDSC 
Myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIBC 
Muscle-invasive bladder cancer 
miRNA 
micro ribonucleic acid 
MRI 
magnetic resonance imaging 


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Abbreviation or 
special term 
Explanation 
mRNA 
messenger ribonucleic acid 
MVAC 
Methotrexate, vinblastine, Adriamycin (doxorubicin), and cisplatin 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung cancer 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 
QoL 
quality of life 
QTc 
the time between the start of the Q wave and the end of the T wave corrected 
for heart rate 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RC 
Radical cystectomy 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation or 
special term 
Explanation 
RNA 
ribonucleic acid 
RT 
Radiation therapy 
SAE 
serious adverse event 
SD 
stable disease 
SID 
subject identification 
sPD-L1 
soluble programmed cell death ligand 1 
SOCS3 
suppressor of cytokine signaling 3 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
TEAE 
treatment-emergent adverse event 
TIL 
tumor infiltrating lymphocyte 
Tmax 
time to peak concentration 
Tmax,ss 
time to peak concentration at steady state 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
TURBT 
Transurethral resection of bladder tumor 
UC 
Urothelial cancer 
ULN 
upper limit of normal 
USA 
United States of America 
WFI 
water for injection 
WHO 
World Health Organization 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
Bladder cancer is the 4th most common cancer amongst men and in 2016, it is estimated that 
approximately 76,960 new cases of bladder cancer will be diagnosed in the United States, with 
approximately 16,390 deaths from this malignancy [1]. Tumors invading the deep muscle of the 
bladder wall are staged as T2, while T3 and T4 lesions invade the perivesical tissue and local 
structures respectively. Transurethral resection of bladder tumor (TURBT) is considered 
standard of care for non-muscle invasive cancers of bladder but 2/3rd of patients experience 
recurrences, with approximately 1/3rd of those eventually requiring radical cystectomy due to 
progression of their disease to muscle invasive bladder cancer. Cisplatin-based chemotherapy 
forms the mainstay of systemic treatment for bladder cancer patients who have locally advanced 
(chemotherapy in neoadjuvant setting) or metastatic disease.  
 
Over the last decade, there has been a tremendous increase in FDA approved therapeutic options 
for various malignancies but choices for bladder cancer have mostly remained unchanged. 
Historically, surgical resection via radical cystectomy, has achieved approximate 5-year 
recurrence-free survival rates of 81%, 68%, 47%, and 44% for pathologic T2, T3a, T3b, and T4a 
tumors, respectively [2]. The 5-year overall survival (OS) rate is 78% for organ-confined, node-
negative disease but this declines to 45% when lymph nodes are involved, though an extended 
lymphadenectomy for node-positive disease may achieve a slight survival advantage [3].The 5-
year OS rate for node-negative patients with extravesical extension is 47% but again falls to 25% 
in node-positive disease. 
 
Neoadjuvant chemotherapy was introduced to treat micrometastatic disease in patients with T2b-
T4a at the time of diagnosis as approximately half of these patients would develop metastatic 
disease within 2 years from surgery [4]. Neoadjuvant chemotherapy followed by radical 
cystectomy (RC) is the gold standard for treatment of patients with T2-4 N0-1 M0 bladder 
cancers. The SWOG (Southwest Oncology Group) trial is one of the most referenced clinical 
trials that support the benefit with neoadjuvant chemotherapy [5]. The patients with node-
negative MIBC (cT2-T4N0M0) were randomized to receive either three cycles of MVAC 
followed by RC (n=153) or to undergo immediate RC (n=154). There was no statistically 
significant difference in 5-yr OS at two-sided testing but the results were promising (MVAC plus 
RC: 57%; RC alone: 43%; two-sided p=0.06). Patients in the neoadjuvant chemotherapy cohort 
were more likely to achieve a pT0 status at the time of RC (48% vs. 15%; p<0.001). Large meta-
analyses showed that cisplatin-based neoadjuvant chemotherapy adds about a 5% 5-year OS 
benefit over cystectomy alone for T2-T4a Nx M0 bladder cancer patients [6]. Most recently two 
prospective clinical trials have shown benefit with accelerated or dose dense neoadjuvant 3-4 
cycles of MVAC chemotherapy followed by RC in patients with T2-4 N1 M0 bladder cancer 
patients [7] [8]. However, both these studies included patients with N1 positive disease with 
nodes <2cm, but N1 positive disease is truly classified as stage IV with high risk for recurrence 
and poor survival so the role of this approach of neoadjuvant chemotherapy in N+ disease is still 
questionable. Despite the advancement in surgical techniques and addition of neoadjuvant 
platinum-based chemotherapy about 50% of these patients will relapse with the development of 
distant metastases and will subsequently die from the disease [2] [5].  
 


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In the setting of operable muscle invasive urinary bladder cancer, selective bladder preservation 
utilizing maximum TURBT, chemotherapy, and radiation therapy results in 5-year disease-
specific survival rates of 60 – 70% [9] [10] [11] [12]. The BC2001 trial which randomized 360 
patients with muscle invasive bladder cancer to radiation therapy with or without chemotherapy 
demonstrated improved outcomes with chemoradiotherapy over radiotherapy alone including 2-
year locoregional disease-free survival of 67% versus 54% and 5-year overall survival of 48% 
versus 35% [13]. Multiple selective bladder preservation Radiation Therapy Oncology Group 
(RTOG) trials incorporated an induction phase of chemotherapy and radiation therapy with a 
planned break of 2 – 4 weeks for repeat cystoscopy to identify non-responders with the 
anticipation for early cystectomy in the event of local progression [Table]. Complete response 
(CR) was seen in about 70% of patients. Recognizing the favorable outcomes with bladder 
preservation, this approach has been evaluated in poor-risk, non-cystectomy candidates in an 
effort to improve disease control. One pilot study evaluating paclitaxel with concurrent radiation 
therapy resulted in 27 of 28 evaluable patients achieving a complete or partial remission with a 
3-year OS of 40% [14]. RTOG 0524 was a phase I/II trial evaluating paclitaxel alone with daily 
radiation therapy and the combination of paclitaxel and trastuzumab for HER2/neu 
overexpression with daily radiation therapy following TURBT for non-cystectomy candidates 
with muscle invasive bladder cancer [15]. The radiation therapy dose and fractionation in RTOG 
0524 was prescribed to deliver 39.6 Gy in 22 daily fractions to a small pelvic field followed by a 
field reduction to treat the whole bladder for an additional 14.4 Gy in 8 daily fractions followed 
by a final boost to the bladder tumor bed for 10.8 Gy in 6 daily (total dose to bladder tumor bed 
was 64.8 Gy in 36 daily fractions). Complete response rates at 12 weeks following treatment 
were 58% in the paclitaxel group and 69% in the paclitaxel with trastuzumab group but acute 
toxicity was observed in about 30% of patients. Most common grade greater than 3 adverse 
events were marrow suppression, diarrhea, and hyponatremia. While the response rates were 
encouraging, adverse events limit applicability in this poor-risk population. 
 
Selected Radiation Therapy Oncology Group (RTOG) Bladder Preservation Trials 
Trial 
Stage 
Inducti
on RT 
(Gy/Fx) 
Induction 
CT 
Planned 
Break 
(weeks)
CR 
Consolidative 
RT (Gy/Fx) 
Consolidative 
CT 
Total RT 
Dose 
(Gy/Fx)
OS 
RTOG 
99-06 
cT2 – 
T4a, N0 
40.3/26 
Cisplatin/ 
paclitaxel 
3 
81% 
24/16 
Cisplatin/Taxol, 
Cisplatin/Gemci
tabine
64.3/42 
56%  
5 yr 
RTOG 
97-06 
cT2 – 
T4a, N0 
40.8/24 
Cisplatin 
3 
74% 
24/16 
Cisplatin 
64.8/40 
61%  
3 yr
RTOG 
95-06 
cT2 – 
T4a, N0 
24/8 
Cisplatin/5
-FU 
3 – 4  
67% 
20/8 
Cisplatin/5-FU 
44/16 
83%  
3 yr
RTOG 
89-03 
cT2 – 
T4a, N0 
39.6/22 
± MCV, 
Cisplatin 
4 
61% 
25.2/14 
Cisplatin 
64.8/36 
49%  
5 yr
RTOG 
88-02 
cT2 – 
T4a N0 
39.6/22 
MCV, 
Cisplatin 
2 
80% 
25.2/14 
Cisplatin 
64.8/36 
62%  
4 yr
RTOG 
85-12 
cT2 – 
T4, N0 
– N2 
40/20 
Cisplatin 
2 
66% 
24/12 
Cisplatin 
64/32 
64%  
3 yr 
 
To date radical cystectomy with bilateral pelvic lymphadenectomy remains the standard of care 
therapy for patients with muscle invasive urothelial cancer (UC) of the bladder. But there are 
significant numbers of patients who are either not able to undergo surgery or are deemed 
unresectable due to locally advanced disease and for this select group of patients the options are 
limited. It is also important to note that most of these studies where neoadjuvant chemotherapy 


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followed by RC or chemoradiation approach were found to be effective were not done on node 
positive disease where current standard of care is systemic chemotherapy followed by salvage 
surgery. This currently represents an unmet need in the management of bladder cancer. We 
propose to study the effect of combining immunotherapy with radiation followed by adjuvant 
immunotherapy in T2-4 N0-2 M0, bladder cancer patients. For both phase Ib and phase II part 
we will include T3-4, N0-1 M0 or Tx N1-2 M0 or T2 N1-2 M0 patients who are either treatment 
naïve but unresectable or unfit for surgery or cisplatin ineligible or become unresectable or unfit 
for surgery post-neoadjuvant chemotherapy. However, T3N0 treatment naïve patients can only 
be included if they are ineligible for cisplatin-based chemotherapy. Please see the eligibility 
criteria for details. In addition, for the phase II part we will also include T2, N0, M0 who are 
ineligible to get cisplatin based chemotherapy.  
 
1.2 
Immunotherapy Treatment in UC 
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 
attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory 
signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such protein, and is 
upregulated in a broad range of cancers with a high frequency, with up to 88% expression in 
some tumor types. In a number of these cancers, including lung [16], renal [17] [18] [19], 
pancreatic [20] [21] [22], and hematologic malignancies [23] tumor cell expression of PD-L1 is 
associated with reduced survival and an unfavorable prognosis. 
 
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumors to help evade detection and elimination by 
the host immune system tumor response. In the lymph nodes, PD-L1 on antigen-presenting cells 
binds to PD-1 or CD80 on activated T cells and delivers an inhibitory signal to the T cell [24] 
[25]. This results in reduced T-cell activation and fewer activated T cells in circulation. In the 
tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and CD80 on activated 
T cells reaching the tumor. This delivers an inhibitory signal to those T cells, preventing them 
from killing target cancer cells and protecting the tumor from immune elimination [26]. 
 
The advances in immunotherapy with the development of immune checkpoint inhibitors have 
revolutionized the care in metastatic melanoma, non-small cell lung cancers [27] [28] [29]. 
Agents targeting PD-1 pathway, such as anti-PD-1, anti-PD-L1 monoclonal antibodies (MAb), 
have also shown promising results in the early phase I clinical studies in patients with UC [30] 
[31]. Powles et al., showed an overall 27% response rate in patients with cisplatin refractory 
advanced UC with the use of anti-PD-L1 MAb, atezolizumab. On May 18, 2016, atezolizumab 
received FDA approval for the treatment of locally advanced or metastatic urothelial cancer who 
have disease progression during or follow platinum-based chemotherapy, or whose disease has 
worsened within 12 months of receiving platinum-based chemotherapy before or after surgery. 
The use of the anti-PD-1 agent, pembrolizumab has also shown comparable efficacy in 
metastatic UC [31]. The FDA approval for atezolizumab was based on results of IMvigor210 
trial that demonstrated that atezolizumab, has around 15% overall response in refractory UC 
patients with a median OS of 7.9 months [32]. This affirms the effectiveness of PD-1 directed 


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blockade in UC and paves the way to test the efficacy of these immune checkpoint inhibitors in 
the earlier stages on UC. There are several other studies investigating the role of immunotherapy 
in early stage bladder cancer with muscle invasive node negative disease as well as upfront 
treatment for metastatic UC. However despite these advances, patients are not cured of their 
disease, hence development of further therapeutic regimens is required to improve survival in 
bladder cancer. 
 
The response of the body’s immune system to an external pathogen or tumor is initiated by 
antigen recognition, differentiation and expansion of activated T-cells followed by immune 
attack. There are two major pathways that play a key role in downregulating the immune attack 
and those include CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1 checkpoints. 
Radiotherapy (RT) is known to cause local tumor control and is used in patients with localized 
disease. RT damages tumor DNA leading to tumor cells apoptosis and necrosis and these dying 
tumor cells release tumor antigens that induces anti-tumor specific immune response [33]. This 
promotes immune responses through stimulation of IFN-gamma and enhances T-cell infiltration. 
RT also causes abscopal effect, where by, in addition to controlling tumor growth at the site it is 
being delivered, it also minimizes, or eradicates cancer at distant sites [33]. The combination of 
an immune check point inhibitor, CTLA-4 and fractionated RT resulted in abscopal effects in 
xenograft models of breast and colon cancer [34]. Preclinical studies have shown that RT can 
enhance the therapeutic efficacy of PD-1/PD-L1 MAbs in triple negative xenograft model [35]. 
There are a few ongoing clinical trials evaluating the role of RT in combination with immune 
checkpoint inhibitors in metastatic solid malignancies (such as NCT02318771), but there are no 
clinical trials evaluating the role of concurrent immunotherapy with RT followed by adjuvant 
immunotherapy in bladder cancer.  
 
1.3 
Durvalumab Treatment 
1.3.1 Durvalumab Background 
Durvalumab is being developed as a potential anticancer therapy for patients with advanced 
solid tumors. 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). Durvalumab is composed of 2 identical heavy chains and 2 identical 
light chains, with an overall molecular weight of approximately 149 kDa. Durvalumab 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. 
1.3.2 Summary of non-clinical experience with durvalumab 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory 
effect of PD-L1 on primary human T cells, resulting in their restored proliferation and release of 
interferon gamma (IFN-γ). Additionally, durvalumab 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 durvalumab 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 


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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 durvalumab. Following 
intravenous (IV) administration, the PK of durvalumab 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 durvalumab. No apparent 
gender differences in PK profiles were observed for durvalumab.  
 
In general, treatment of cynomolgus monkeys with durvalumab was not associated with any 
durvalumab -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: durvalumab 
immune complexes were identified in a subsequent non-GLP, investigative 
immunohistochemistry study. Similar observations were reported in cynomolgus monkeys 
administered human mAbs unrelated to durvalumab. 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 durvalumab.  
 
Finally, data from the pivotal 3-month GLP toxicity study with durvalumab in cynomolgus 
monkeys showed that subchronic dosing of durvalumab was not associated with any adverse 
effects. Therefore, the NOAEL of durvalumab in all the general toxicity studies was considered 
to be 100 mg/kg, the highest dose tested in these studies. In addition to the in vivo toxicology 
data, no unexpected membrane binding of durvalumab to human or cynomolgus monkey tissues 
was observed in GLP tissue cross-reactivity studies using normal human and cynomolgus 
monkey tissues. 
 
1.3.3 Summary of clinical experience with durvalumab 
As of the DCO dates (15Apr2015 to 18Sep2015, Durvalumab IB Version 9.0), a total of 1,910 
subjects have been enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 
sponsored and 10 collaborative studies. Of the 1,910 subjects, 1,279 received durvalumab 
monotherapy, 454 received durvalumab in combination with tremelimumab or other anticancer 
agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 163 have been treated with 
blinded investigational product. No studies have been completed or terminated prematurely due 
to toxicity. 


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1.3.4 Pharmacokinetics and Product Metabolism  
Study CD-ON-durvalumab-1108: As of 09 Feb2015, PK data were available for 378 subjects 
in the dose-escalation and dose-expansion phases of Study CD-ON-durvalumab-1108 following 
treatment with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks 
(Q3W). The maximum observed concentration (Cmax) increased in an approximately dose-
proportional manner over the dose range of 0.1 to 15 mg/kg. The area under the concentration-
time curve from 0 to 14 days (AUC0-14) increased in a greater than dose-proportional manner 
over the dose range of 0.1 to 3 mg/kg and increased dose-proportionally at ≥ 3 mg/kg. These 
results suggest durvalumab exhibits nonlinear PK likely due to saturable target-mediated CL at 
doses < 3 mg/kg and approaches linearity at doses ≥ 3 mg/kg. Near complete target saturation 
(soluble programmed cell death ligand 1 [sPD-L1] and membrane bound) is expected with 
durvalumab ≥ 3 mg/kg Q2W. Exposures after multiple doses showed accumulation consistent 
with PK parameters estimated from the first dose. In addition, PK simulations indicate that 
following durvalumab 10 mg/kg Q2W dosing, > 90% of subjects are expected to maintain PK 
exposure ≥ 40 µg/mL throughout the dosing interval. 
 
As of 09 Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 
388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg 
cohort) were ADA positive with an impact on PK/pharmacodynamics in 1 subject in the 
3 mg/kg cohort. 
1.3.5 Safety  
The safety profile of durvalumab 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 durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, 
neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, 
pancreatitis is an important potential risk particularly with durvalumab and tremelimumab 
combination therapy. These events are manageable by available/established treatment 
guidelines as described in the study protocols. 
 
AEs reported with durvalumab monotherapy in key clinical studies are described below. 
1.3.6 Adverse Event Profile of Durvalumab Monotherapy 
 
Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 
694 subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study 
CD-ON-durvalumab-1108 has been broadly consistent with that of the overall 1,279 subjects 
who have received durvalumab monotherapy (not including subjects treated with blinded 
investigational product) across the clinical development program. The majority of treatment-
related AEs were manageable with dose delays, symptomatic treatment, and in the case of 
events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity. As of 07 May2015, among the 694 subjects treated with durvalumab 
10 mg/kg Q2W in Study CD-ON-durvalumab-1108, a total of 378 subjects (54.5%) experienced 
a treatment-related AE, with the most frequent (occurring in ≥ 5% of subjects) being fatigue 


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(17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash 
(6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 
in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment-related ≥ Grade 3 
events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased 
aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase 
(GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and 
colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects 
had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, 
neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related Grade 5 
event (pneumonia). Treatment-related serious adverse events (SAEs) that occurred in ≥ 2 
subjects were colitis and pneumonitis (3 subjects each). A majority of the treatment-related 
SAEs were ≥ Grade 3 in severity and resolved with or without sequelae. AEs that resulted in 
permanent discontinuation of durvalumab were considered as treatment related in 18 subjects 
(2.6%), with colitis being the most frequent treatment-related AE resulting in discontinuation 
(3 subjects). A majority of the treatment-related AEs resulting in discontinuation of durvalumab 
were ≥ Grade 3 in severity and resolved with or without sequelae. 
 
The results from this phase I study has led FDA to grant breakthrough therapy designation to 
durvalumab in February 2016, for the treatment of patients with PD-L1 positive inoperable or 
metastatic urothelial bladder cancer whose tumor has progressed during or after one standard 
platinum-based regimen. Durvalumab is currently FDA approved for metastatic patients post 
cisplatin.  
 
Encouraging results from this study has led to the design of a phase III study in bladder cancer. 
DANUBE is a phase III study that is evaluating the efficacy of durvalumab alone vs. 
durvalumab plus anti-CTLA4 Mab, tremelimumab vs. standard of care in 1st line setting for 
metatstatic chemo naïve cisplatin eligible and cisplatin ineligible patients. The results are 
expected by 2018.  
 
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in 
Study CD-ON-durvalumab-1108 is generally consistent with that of 
Study D4191C00003/ATLANTIC in subjects with locally advanced or metastatic non-small-
cell lung cancer (NSCLC) treated with durvalumab 10 mg/kg Q2W. As of 05May2015, 264 of 
303 subjects (87.1%) reported any AE in Study D4191C00003/ATLANTIC. Overall, events 
reported in ≥ 10% of subjects were dyspnea (18.8%), fatigue (17.8%), decreased appetite 
(17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), and nausea (11.2%). Nearly two-
thirds of the subjects experienced AEs that were Grade 1 or 2 in severity and manageable by 
general treatment guidelines as described in the current durvalumab study protocols. Grade 3 or 
higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 subjects (42.2%) 
reported AEs that were considered by the investigator as related to investigational product. 
Treatment-related AEs (all grades) reported in ≥ 2% of subjects were decreased appetite (6.6%); 
fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, 
hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and vomiting 
(2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects were pneumonitis (3 subjects) 
and increased GGT (2 subjects). There was no treatment-related Grade 4 or 5 AEs. Ninety-four 
of 303 subjects (31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of subjects were 


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dyspnea (6.6%); pleural effusion, general physical health deterioration (2.3% each); pneumonia 
(2.0%); hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, respiratory failure, 
disease progression (1.0% each). Nine subjects had an SAE considered by the investigator as 
related to durvalumab. Each treatment-related SAE occurred in 1 subject each with the 
exception of pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have 
died due to an AE (pneumonia [3 subjects]; general physical health deterioration, disease 
progression, hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, 
cardiopulmonary arrest [verbatim term (VT)], hepatic failure, and sepsis [1 subject each]). None 
of these events was considered related to durvalumab. Twenty-three of 303 subjects (7.6%) 
permanently discontinued durvalumab treatment due to AEs. Events that led to discontinuation 
of durvalumab in ≥ 2 subjects were dyspnea, general physical health deterioration, and 
pneumonia. Treatment-related AEs that led to discontinuation were increased ALT and 
increased hepatic enzyme, which occurred in 1 subject each. 
 
1.3.7 Efficacy  
 
Study CD-ON-durvalumab-1108: Overall, 456 of 694 subjects treated with durvalumab 
10 mg/kg Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, 
measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan). In PD-L1 unselected patients, the objective 
response rate (ORR), based on investigator assessment per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in bladder 
cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in triple-
negative breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). 
PD-L1 status was known for 383 of the 456 response evaluable subjects. Across the PD-L1-
positive tumors, ORR was highest for bladder cancer, advanced cutaneous melanoma, 
hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), and 
squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the PD-L1-positive 
subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 
86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
 
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 [5] 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-durvalumab-1161: Of the 65 subjects with metastatic or unresectable 
melanoma treated with the combination of durvalumab 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%.  
 


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1.3.8 Fixed Dosing  
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 
mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations 
(5th, median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 
patients were simulated using body WT distribution of 40–120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state 
PK concentrations with slightly less overall between-subject variability with fixed dosing 
regimen.   
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens for monotherapy. Based on average 
body WT 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 recommend only for subjects with 
> 30kg total 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 (see Documents/Info tab 
of the EDC for dose calculations on subjects less than or equal to 30 kg).   
 
1.4 
Rationale for combining durvalumab with RT 
Despite advances in immunotherapeutic options for cancer patients, only a select group of 
patients benefit from this strategy. Hence trials of combinational approaches are needed to 
enhance the efficacy of these immunotherapeutic agents. Radiation induces immunogenic cell 
death comprising of 3 main steps- cell surface transfer of calreticulin, extracellular release of 
high mobility group protein-B1 and release of ATP [36] [37] [38]. Immunogenic cell death 
causes production of neo-antigens that causes activation of tumor-specific T-cell activation and 
in addition ionizing radiation causes upregulation of various pro-inflammatory signals (CXCL9, 
CXCL10, CXCL16, IFN, interleukin 1β, MHC-1) that play a key role in immune-regulatory 
pathway, leading to improved anti-tumor immunity. Verbrugge et.al. demonstrated in animal 
model that combination of RT with concominant and adjuvant anti PD-1 agent can enhance the 
release of tumor antigens thus synergistically improving the anti-tumor immunity [35].  RT is 
known to cause local control of tumor but it also causes abscopal effect, where by, in addition to 
controlling tumor growth at the site it is being delivered, it minimizes, or eradicates cancer at 
distant sites [33]. The combination of an immune check point inhibitor, CTLA-4 and fractionated 
RT resulted in abscopal effects in xenograft models of breast and colon cancer [34]. There are 
various clinical trials evaluating the efficacy of combining radiation therapy with checkpoint 
inhibitors. Koller et.al. (personal communication with the author) retrospectively compared 70 
patients with melanoma who had ipilimumab and concurrent radiation therapy vs 31 who had 
ipilimumab alone and found a higher CR rate (25.7& vs 6.45% p=0.04 and an improved OS (21 
vs 10 months p=0.025) in the concurrent group suggesting that concurrent radiotherapy can 
improve the outcomes of check-point inhibitor therapy. The combination was well tolerated with 
no grade 3 or more side effects. The preliminary evidence suggests that combining radiation 


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therapy with immune-checkpoint inhibitor could enhance the efficacy of immunotherapeutic 
agents in cancer.  
 
Our study is combining anti-PD-L1 agent, durvalumab with radiation therapy followed by 12 
months of adjuvant durvalumab for patients with UC of bladder who have locally advanced 
disease with no distant metastases. The current standard of care for locally advanced node 
negative UC of bladder is neoadjuvant chemotherapy followed by surgery whereas 
chemoradiation remains the second best option for these patients. Despite the advancement in 
surgical techniques and addition of neoadjuvant platinum-based chemotherapy about 50% of 
these patients will relapse with the development of distant metastases and will subsequently die 
from the disease. It is well-recognized that improved survival is associated with absence of 
residual disease in the surgical specimen after neoadjuvant chemotherapy but at best 
approximately 30-35% of patients achieve pathological remission with these strategies [5] [13]. 
The 5-year OS is approximately 82-85% in those who achieve a pT0 stage as opposed to 40-45% 
in those who have residual disease at the time of cystectomy [2]. Given the high rate of 
recurrences and poor survival associated with patients who do not achieve pathological complete 
response, there is an urgent need to develop a treatment strategy to prevent the development of 
metastases.  
 
Patients who have node positive disease are truly stage IV per American Joint Committee of 
Cancer (AJCC) 6th and 7th edition guidelines. These patients are very high risk for recurrence and 
have worse overall survival [2]. Earlier studies have demonstrated that node positive locally 
advanced UC of bladder patients, who got RC after achieving PR post 6 cycles of systemic 
chemotherapy, lived longer when compared to those who did not get surgery [39].  But the role 
of neoadjuvant chemotherapy and surgery in stage IV disease is poorly defined and until more 
definitive data from well-designed phase 3 study shows similar outcomes when compared to 
node negative disease, the standard of care should be systemic treatment. Systemic 
chemotherapy in stage IV disease gives a median OS of 13-15 months at best and for patients 
who progress on or after platinum based therapy, treatment options are limited. Hence more 
research for better therapeutic approach is needed in this select group of patients to devise better 
therapeutic options.  
 
1.5 
Hypothesis:  
We propose a phase I/II clinical trial of concurrent and adjuvant anti-PD-L1 antibody, 
durvalumab in combination with radiation therapy in patients who have UC of bladder (T2-4, 
N0-2, M0) treatment naïve or post neoadjuvant chemotherapy who are either unresectable OR 
unfit for surgery or have refused surgery (post neoadjuvant chemo).   
 
We hypothesize that RT will enhance the therapeutic efficacy of immunotherapy. Since the 
current standard of care for patients who are locally advanced and are not candidates for surgery 
is chemotherapy or chemoradiation, we plan to combine radiation with anti-PD-L1 antibody. We 
postulate that this combination of durvalumab, an anti-PD-L1 antibody with radiation will result 
in better progression free survival and disease control rate.  
 
 
 


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1.5.1 Rationale for Objectives: 
 
Primary Objectives:  
 
Phase Ib: 
 To assess the safety of combining durvalumab with RT: The phase Ib part of the study 
will help us determine the safety of combining the standard dose of RT with durvalumab. 
There is evidence from our retrospective study that the combination of RT plus immune 
checkpoint inhibitor is safe and is better when compared to immune checkpoint inhibitor 
alone (Koller et.al.- personal communication). There are ongoing studies in various solid 
tumor types evaluating this similar concept but there are no studies currently evaluating 
the efficacy of combining standard RT with PD-L1 MAb in bladder cancer. Thus, our 
phase Ib part will help us determine the safety for this unique combination.  
 
Phase II:  
 To estimate the progression free survival (PFS) rate at 1 year: We will be evaluating the 
efficacy of treating patients with locally advanced UC of bladder (T2-4, N0-2, M0) with 
concurrent durvalumab and RT to bladder and involved lymph node followed by adjuvant 
durvalumab. We believe that PFS rate at 1 year will be the surrogate end point for PFS 
and OS and will help us evaluate efficacy with this treatment strategy.  
 To estimate the disease control rate (DCR) (DCR=complete response [CR]+partial 
response [PR] +stable disease [SD]) to concurrent durvaRT followed by durvalumab by 
modified RECIST 1.1: We will be determining the DCR, defined for this study as rates of 
patients achieving CR, PR or SD, post completion of concurrent durvaRT+ adjuvant 
durvalumab per modified RECIST 1.1 criteria.  
 
Secondary Objective(s): 
 
Phase Ib: 
 Estimate the DCR post completion of concurrent durvaRT by modified RECIST 1.1: We 
will be determining the disease control rate, defined as percentage of patients achieving 
CR, PR, SD post completion of concurrent durvaRT in the phase I part of the study. This 
will give us some preliminary evidence for efficacy of durvaRT combination.  
 To correlate the expression of PD-L1 on immunohistochemistry at pre-treatment (TURBT 
specimen if possible) and post- durvaRT treatment (cystoscopy-biopsy 2-3 weeks post 
durvaRT) with DCR: We will be determining the correlation between PD-L1 expression 
on tumor and tumor infiltrating cells when compared to clinical outcome (DCR). 
Previous study by a PD-L1 MAb has suggested PD-L1 expression playing a potential role 
as a predictive biomarker for response in metastatic setting in bladder cancer to immune 
checkpoint blockade [30]. This is an important end-point to determine the role of PD-L1 
status as an effective predictive biomarker for response to durvalumab. 
 
Phase II: 
 Estimate the median progression free survival (PFS) time: We will be determining the 
median PFS for our cohort and will compare it to the available median PFS from 
historical controls. Since this is a single arm phase II study with an innovative approach 


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for patients with locally advanced UC of bladder, who are not fit for surgery, there is 
limitation in having an active comparator arm.  
 Estimate the rate of complete remission (CR) post durvaRT by modified RECIST 1.1: 
Rate of CR is one of the secondary objectives for phase II part of this study. This will 
help us determine the actual effectiveness of durvaRT approach. CR will be determined 
with the help of imaging and cystoscopy post completion of durvaRT per modified 
RECIST 1.1.  
 Estimate the overall survival (OS): OS is defined, as time from start of treatment to the 
date of death due to any cause, or to the date of censoring at the last time the subject was 
known to be alive in intention-to-treat population. OS is one of the secondary objectives 
of this study. This is an immunotherapy based clinical trial and it is prudent to determine 
the OS to reflect the long-term benefit from this therapeutic approach.  
 
Exploratory Objective(s): 
 To explore the correlation between the PD-1, PD-L1 and FOXP3 (T-regulatory cells) 
expression on immunohistochemistry at pre-treatment (TURBT specimen) and post- 
durvaRT treatment (cystoscopy-biopsy 2-3 weeks post durvaRT) with DCR, PFS and OS: 
We will explore the correlation between PD-L1 expression on tumor and tumor 
infiltrating cells when compared to clinical outcome (DCR, PFS, OS). Previous study by 
a PD-L1 MAb has hinted towards PD-L1 playing a potential role as a predictive 
biomarker for response in metastatic setting in bladder cancer to immune checkpoint 
blockade [30]. This is an important end-point to determine the role of PD-L1 status as an 
effective predictive biomarker for response to durvalumab. In addition, we will perform 
IHC scores for PD-1, FOXP3 to determine its correlation with tumor stage and clinical 
outcome. 
 We will also explore if the combination of RT with durvalumab increases the PD-L1+ 
status in tumor specimen when compared to baseline.  We will compare the expression of 
PD-L1 on immunohistochemistry at pre-treatment (TURBT specimen if possible) and 
post- durvaRT treatment (cystoscopy-biopsy 2-3 weeks post durvaRT). There is 
preliminary evidence from pre-clinical data and retrospective study that radiation will 
enhance the efficacy of PD-1 MAb therapy. We will explore if radiation will upregulate 
the PD-L1 expression.  
 Explore the correlation of PD-1 expression on T cells from peripheral blood with clinical 
outcomes: Peripheral blood will be collected at baseline, post completion of durvaRT and 
post completion of adjuvant durvalumab. Expression of PD-1 on CD4+ and CD8+ T cells 
will be assessed by flow cytometry. Correlation between the level of PD-1 expression and 
clinical outcomes (DCR, PFS, OS) will be analyzed. 
 To explore correlation of next generation sequencing (NGS) of tumors and blood at 
pretreatment and at post durvaRT with response rate for durvaRT +adjuvant 
durvalumab. As part of NGS, RNA-seq would be performed and we would attempt to 
perform immunosubtyping based on expression data, as well as perform deconvolution 
analysis in an effort to understand changes in tumor immune cell inflammation. In 
addition, we will do next generation sequencing of urine cell free DNA at pretreatment 
and will correlate with tumor sequencing at pretreatment stage##: We will explore the 
correlation between mutational statuses- upregulation of specific mutation/pathway, 
mutational burden with clinical outcome. We will also do NGS at baseline on ucfDNA 


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and compare it to the tumor NGS for specificity and sensitivity. This will help us 
determine the role of circulating DNA in urine as a non-invasive surrogate marker for 
tumor biopsies.  
 To explore the correlation of plasma cytokines such as IFN-γ level with clinical 
outcomes##. Peripheral blood will be collected prior to durvaRT, post completion of 
durvaRT and post treatment of adjuvant durvalumab. Inflammatory cytokines such as 
IFN-γ concentration in plasma will be assessed by Bead-based immunoassays. In 
addition, intracellular cytokine release by CD4 and CD8 T cells, and their phenotypic 
subsets, will be assessed by flow cytometry. Correlation between the level of cytokine 
production and clinical outcomes (RR, PFS, OS) will be analyzed. 
 
##: Contingent upon available funding.  
 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objectives 
 
Phase Ib: 
1. To assess the safety of combining durvalumab with RT.  
 
Phase II:  
1. To estimate the progression free survival (PFS) rate at 1 year  
2. To estimate the DCR to concurrent durvaRT followed by durvalumab.  
 
2.1.2 Secondary Objectives 
 
Phase Ib: 
1. Estimate the DCR post completion of concurrent durvaRT 
2. To correlate the expression of PD-L1 on immunohistochemistry at pre-treatment 
(TURBT specimen if possible) and post- durvaRT treatment (cystoscopy-biopsy 2-3 
weeks post durvaRT) with DCR. 
 
Phase II: 
1. Estimate the median progression free survival (PFS) time.  
2. Estimate the rate of complete remission (CR) post durvaRT by modified RECIST 1.1  
3. Estimate the overall survival (OS) 
 
2.1.3 Correlative/Exploratory Objectives 
1. To explore the correlation between the PD-1, PD-L1 and FOXP3 (T-regulatory cells) 
expression on immunohistochemistry pre-treatment (TURBT specimen) and post- 
durvaRT treatment (cystoscopy-biopsy 2-3 weeks post durvaRT) with DCR, PFS and OS. 
2. We will also explore if the combination of RT with durvalumab increases the PD-L1+ 
status in tumor specimen when compared to baseline.  We will compare the expression of 
PD-L1 on immunohistochemistry at pre-treatment (TURBT specimen if possible) and 
post- durvaRT treatment (cystoscopy-biopsy 2-3 weeks post durvaRT). 


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3. To explore the correlation of PD-1 expression on T cells from peripheral blood with 
clinical outcomes. Peripheral blood will be collected at pretreatment, post durvaRT, and 
post completion of treatment with adjuvant durvalumab. 
4. To explore correlation of next generation sequencing (NGS) of tumors and blood at 
pretreatment and at post durvaRT with response rate for durvaRT +adjuvant durvalumab. 
As part of NGS, RNA-seq would be performed and and we would attempt to perform 
immunosubtyping based on expression data, as well as perform deconvolution analysis in 
an effort to understand changes in tumor immune cell inflammation. In addition, we will 
do next generation sequencing of urine cell free DNA at pretreatment and will correlate 
with tumor sequencing at pretreatment stage.  
5. To explore the correlation of plasma cytokines such as IFN-γ level with clinical 
outcomes. Peripheral blood will be collected prior to durvaRT, post completion of 
durvaRT and post treatment of adjuvant durvalumab. Inflammatory cytokines such as 
IFN-γ concentration in plasma will be assessed by Bead-based immunoassays. In 
addition, intracellular cytokine release by CD4 and CD8 T cells, and their phenotypic 
subsets, will be assessed by flow cytometry. Correlation between the level of cytokine 
production and clinical outcomes (RR, PFS, OS) will be analyzed. 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
 
Phase Ib: 
1. To assess the safety of combining durvalumab with RT in that DLT rate is lower than 
than 33%.  
 
Phase II: 
1. Estimate the progression free survival (PFS) rate at 1 year. Progression free survival rate 
at one year is defined as the probability that a patient remains free of progression of 
disease (SD+CR+PR) by modified RECIST 1.1 and cystoscopy at 1 year from the start of 
durvalumab treatment, D1 of durvaRT.  
2. To estimate the DCR to concurrent durvaRT followed by durvalumab. DCR will be 
defined for this study as rates of patients achieving CR, PR or SD post completion of 
concurrent durvaRT and adjuvant durvalumab. Response will be determined by modified 
RECIST 1.1. 
 
2.2.2 Secondary Endpoints 
 
Phase Ib: 
1. Estimate the DCR post completion of concurrent durvaRT.  
2. To correlate the expression of PD-L1 on immunohistochemistry at pre-treatment 
(TURBT specimen if possible) and post- durvaRT treatment (cystoscopy-biopsy 2-3 
weeks post durvaRT) with DCR 
 
Phase II: 
1. Estimate the median progression free survival (PFS) time. Median PFS for this cohort 
will be calculated.  
2. Estimate the rate of complete remission (CR) post durvaRT by modified RECIST 1.1 


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3. Estimate the overall survival (OS) defined as time from start of treatment, D1, to the date 
of death due to any cause, 
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
Phase Ib subjects must meet the following inclusion criteria: 
 Locally advanced urothelial cancer of bladder with any of the following: 
a) T3-4, N0-2 M0, OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR 
medically unfit for surgery* OR cisplatin ineligible**. T3 N0 M0 patients can be 
included if they are cisplatin ineligible**. 
b) Patients who have T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-neoadjuvant 
chemotherapy who become unresectable OR are medically unfit for surgery*  
 
Phase II subjects must meet the following inclusion criteria: 
 Locally advanced urothelial cancer of bladder with any of the following:  
a) T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR 
medically unfit for surgery* OR cisplatin ineligible**. T3 N0 M0 patients can be be 
included if they are cisplatin ineligible**. 
b) T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients post-neoadjuvant 
chemotherapy who become unresectable OR medically unfit for surgery*. (Please note: 
the stage of tumor is based on prechemotherapy status at the time of diagnosis) 
 
T2, N0, M0 who are ineligible to get cisplatin based chemotherapy**  
 
T2 N0 M0 patients who are treatment naïve or post neoadjuvant chemotherapy but are unfit 
for surgery* may also be enrolled.  
 
*Unfit for surgery is based on patient’s cardiac status or pulmonary status or any co-morbidity 
that can put patients at high risk for complications during or after surgery. “Unfit for surgery” 
status has to be determined by treating surgeon. 
 
**Cisplatin ineligibility is defined by the presence of one or more of the following: 
 Impaired renal function (GFR ≥ 30 but ≤ 60 cc/min). GFR should be assessed by direct 
measurement (i.e. creatinine clearance or ethylenediaminetetra-acetate) or, if not 
available, by calculation from serum/plasma creatinine by Cockroft-Gault equation. 
 Grade ≥ 2 Hearing Loss (hearing loss measured by audiometry of 25 dB at two 
contiguous frequencies) 
 Grade ≥ 2 peripheral neuropathy  
 ECOG Performance Status of 2 
 Solitary Kidney 
 Any other medical condition that makes patient cisplatin ineligible based on assessment 
by treating Oncologist, such as severe CAD, congestive heart failure, etc.  
 
In addition to the criteria above, all subjects must meet all of the following applicable inclusion 
criteria to participate in this study: 
 


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1. Written informed consent and HIPAA authorization for personal 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. 
2. Age > 18 years at the time of informed consent. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
4. Life expectancy of >6 months per treating physician. 
5. Subjects must have archival tissue available from previous TURBT (preferred) or lymph 
node core biopsy within 8 weeks of treatment or be assessed by the treating urologist to 
undergo maximal TURBT. The extent of TURBT may vary for each patient and will be 
determined by the treating urologist. Further, the treating urologist will decide if performing 
the TURBT is clinically appropriate. If the potential subject does not have tumor amenable to 
biopsy, there is insufficient tissue for PD-L1 testing or is not clinically appropriate for 
TURBT, enrollment must be discussed with the sponsor-investigator on a case by case basis. 
6. Histologically proven pure or mixed urothelial carcinoma of bladder. Small cell histology 
would be excluded 
7. Adequate organ and marrow function as defined below:  
a) Hemoglobin ≥ 9.0 g/dL 
b) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
c) Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
d) Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not apply to 
subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia 
that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), 
who will be allowed only in consultation with their physician. 
e) AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal. 
f) Serum creatinine CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 
1976) or by 24-hour urine collection for determination of creatinine clearance: 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL)
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        x 0.85 
72 x serum creatinine (mg/dL)
8. Females of childbearing potential must have a negative urine and serum pregnancy test 
within 3 days of study registration. 
NOTE: Female subjects are considered of child bearing 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. 
9. 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: 
 
Exclusion criteria for both phase Ib and phase II subjects 


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1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).  
2. Participation in another clinical study with an investigational product within 2 weeks prior to 
registration. 
3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab. 
4. Previous systemic immunotherapy. Previous use of intravesical BCG is acceptable. 
5. History of another primary malignancy except for: 
a) Malignancy treated with curative intent and with no known active disease ≥3 years before 
the first dose of study drug and of low potential risk for recurrence. However adequately 
treated prostate cancer >2 years ago with no significant change in PSA for past 6 months 
can be included. Patients with a history of prostate cancer must not have any definitive 
radiation therapy to prostate area. 
b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
c) Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in 
situ. 
d) Previously adequately treated urothelial cancer of upper urinary tract T1 or CIS with no 
muscle invasion 
6. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine 
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other 
investigational agent) within 14 days prior to the first dose of study drug (14 days prior to the 
first dose of study drug for subjects who have received prior TKIs [e.g., erlotinib, gefitinib 
and crizotinib] and within 6 weeks for nitrosourea or mitomycin C).  
7. Mean QT interval corrected for heart rate (QTc) ≥470 ms on electrocardiogram (ECG) using 
Frediricia’s Correction. 
8. Current or prior use of immunosuppressive medication within 28 days before the first dose of 
durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or 
an equivalent corticosteroid. 
9. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.  (Subjects 
with irreversible toxicity that is not reasonably expected to be exacerbated by the 
investigational product may be included (e.g., hearing loss, peripheral neuropathy). 
10. Any prior Grade ≥3 immune-mediated adverse event (imAE) while receiving any previous 
immunotherapy agent, or any unresolved imAE >Grade 1. 
11. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with 
vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 
years) are not excluded. Patients with h/o completely resolved childhood asthma or atopy will 
not be excluded. Patients with well-controlled hypothyroidism on thyroxine replacement will 
be eligible as well.  
12. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis).  
13. History of and/or confirmed pneumonitis.   
14. History of primary immunodeficiency. 
15. History of allogeneic organ transplant. 
16. History of hypersensitivity to durvalumab or any excipient. 
17. History of hypersensitivity to the combination or radiation therapy. 


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18. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including 
any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human 
immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit 
compliance with study requirements or compromise the ability of the subject to give written 
informed consent. 
19. Known history of previous clinical diagnosis of tuberculosis. 
20. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of 
starting treatment with durvalumab. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
21. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive 
potential who are not employing an effective method of birth control. For this study male or 
female patients of reproductive potential need to employ two highly effective and acceptable 
forms of contraception throughout their participation in the study and for 90 days after last 
dose of study drug 
22. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
23. Brain metastases or history of leptomeningeal carcinomatosis. 
24. Subjects with uncontrolled seizures. 
25. Previous definitive radiation to pelvic area. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through BTCRC Administrative Headquarters’ electronic data 
capture (EDC) system OnCore. A subject is considered registered when an ‘On Study’ date is 
entered into OnCore. 
 
Subjects must be registered prior to starting protocol therapy. Subjects must begin therapy within 
14 days of registration.  
 
Subjects who do not begin study treatment: If a subject signs consent, is registered to the study, 
and later is not able to begin the planned study treatment, for whatever reason, the subject will be 
considered a screen failure and will be replaced. The reason for removal from study will be 
clearly indicated in EDC system. The subject will then be treated off study, per physician’s 
discretion. 
 
Subjects who are incorrectly enrolled but have not initiated treatment should be withdrawn from 
the study and will be labeled as screen failure. 
 
Subjects who have been enrolled in error and have initiated treatment should be discussed with 
the sponsor-investigator. It will be at the discretion of sponsor-investigator to decide about the 
safety of continuing treatment for that patient. If the sponsor-investigator decides to exclude the 
patient from the study, that subject will not be counted for any statistical analyses. Please note 


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that these subjects must be excluded from the phase I study analyses and treatment on the clinical 
trial should be discontinued. 
 
 


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5. 
TREATMENT PLAN 
 
5.1 
Overview of Study Design 
This is a single arm, open-label phase Ib/II study of durvaRT followed by adjuvant durvalumab. 
Phase Ib will be conducted to determine the safety of durvalumab in combination with RT. Phase 
II will estimate the 1-year PFS and DCR. 
 
5.2 
Number of Subjects 
A total of 26 subjects will be enrolled on both phases. 
 
Phase Ib: Up to 6 subjects 
Phase II: 26 subjects (including 6 rolled over from Phase Ib). 
 
The 6 patients in Phase Ib will be rolled over and be combined with patients in Phase II in the 
analysis. 
 
5.3 
Durvalumab Phase Ib Study 
 
5.3.1 DurvaRT 
 Each cycle of concurrent durvalumab with RT will be Q28 days (Q4 weeks) for a maximum 
of 2 doses during concurrent radiation therapy. Durvalumab will be started on day 1 of RT. 
The dose of durvalumab may be given either before (preferred) or after the dose of RT.  
 Day 1 of concurrent durvaRT treatment should start on a Monday, Tuesday or Wednesday. 
 
Phase Ib 
Cohort 
# of 
Subjects 
Durvalumab IV 
RT 
1 
Up to 6 
2 doses Q4 weeks; 
1500mg if >30kg OR 
20mg/kg if ≤ 30kg 
64.8 Gy, 36 daily fractions on 
weekdays over about 7 weeks 
 
DOSE: DurvaRT – concurrent durvalumab and RT 
 Durvalumab: 1500mg q 4 weeks if patients are >30kg OR 20mg/kg q 4 weeks if ≤ 30kg 
total body weight intravenously for 2 doses.  
 RT: RTOG dose fractionation and field design will be 64.8 Gy in 36 daily fractions using 
a sequential field reduction technique as described below.  
 Number of patients: up to 6 
 
Given the safety is not dose dependent; no dose de-escalation will be allowed 
 
5.3.2 Dose and Safety Definition  
Patients enrolled in phase Ib during durvaRT will be managed with the rules as listed below.  
 
Three patients will be enrolled initially. If 2 or more patients (out of 3) experience dose-limiting 
toxicity (DLT), the combined treatment will be considered unsafe. Otherwise, an additional 3 
patients will be treated at the same dose. If 0 or 1 patient experience DLT, the dose of 
durvalumab in section 5.3 above will be deemed safe for phase 2 part of the study. If, however, 2 


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or more patients (out of 6) experience DLT, the combined treatment will be considerd unsafe. In 
this case, durvalumab will be permanently discontinued and the subjects followed up per 
protocol. 
 
5.3.3 Definition of Dose Limiting Toxicity 
Subjects who do not remain on the study up to this time for reasons other than DLT will be 
replaced with another subject at the same dose level.  
 
A DLT will be defined as any treatment-related toxicity described below that occurs during the 
durvaRT phase (7 weeks). The following will be DLTs: 
 Any Grade 4 imAE* 
 Any ≥ Grade 3 colitis 
 Any grade of immune-mediated neurotoxicity. 
 Any Grade 3 non-infectious pneumonitis irrespective of duration 
 Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation 
of maximal supportive care 
 Any Grade 3 imAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 
within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days 
 Grade 3 liver transaminase elevation with concurrent total bilirubin > 2 × ULN  
 Any grade of febrile neutropenia regardless of duration or reversibility 
 Any ≥ Grade 3 non-imAE, except for the exclusions listed below 
 
The following conditions are excluded from the DLT definition:  
 Grade 3 fatigue lasting ≤ 7 days 
 Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic 
 Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) 
 Concurrent vitiligo or alopecia of any AE grade 
 Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
 Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days.  
 Grade 3 or 4 lymphopenia 
 Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention and improves by at least 1 grade within 3 days 
 Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days 
 Transient asymptomatic laboratory abnormalities that do not require hospitalization 
 
* Immune-related AEs (imAE) are defined as AEs of an immune nature (ie, inflammatory) in the 
absence of a clear alternative etiology.  
 


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In the absence of a clinically significant abnormality, repeat laboratory testing will be conducted 
to confirm significant laboratory findings prior to designation as a DLT.  
 
DLTs will be counted based on the number of subjects with DLT, not the absolute number of 
DLTs. No single subject can trigger more than one DLT event. Additional subjects will not be 
enrolled until the initial subjects complete all planned treatment for durvaRT (defined as 2 doses 
of Q4 week durvalumab, along with radiation=7 weeks) and are able to start cycle 2 of 
durvalumab during combined durvaRT therapy with no more than a 3-week delay. Grade 3 or 4 
adverse events that persist for more than 7 days should result in discontinuation from study 
treatment. 
 
5.3.4 Adjuvant durvalumab 
 Post-concurrent durvaRT, single agent durvalumab will be given every 4 weeks for a 
total period of up to 12 months (1500 mg Q 4 weeks if patients are >30kg OR 20mg/kg Q 
4 weeks if ≤ 30kg total body weight).  
 Adjuvant durvalumab treatment will be started 3-4 weeks post completion of durvaRT. 
 Subjects who have a dose interruption due to toxicity at any point in the first 12 months 
of treatment may resume treatment but the 12-month treatment period may not be 
extended. 
 Please note that we already have the safety data for using durvalumab as monotherapy in 
metastatic bladder cancer. Subjects will receive a maximum of 13 doses (or a 12-month 
treatment period, whichever occurs first) of Q4 week durvalumab during the entire course 
of adjuvant treatment.  
 
5.4 
Durvalumab Phase II Study 
Once the safety of durvalumab with RT has been established, we will open the phase II part of 
this study.  
 
5.4.1 DurvaRT 
Patients will receive durvalumab Q4 weeks (2 doses) during RT (about 7 weeks).  
 
 Each cycle of concurrent durvalumab with RT will be Q28 days (Q4 weeks) for a 
maximum of 2 doses during the entire concurrent radiation therapy. Durvalumab will be 
started on day 1; RT will be started on day 1 or 2. The dose of durvalumab may be given 
either before (preferred) or after the dose of RT.  
 Phase II durvalumab dose: 1500mg q 4 weeks if patients are >30kg OR 20mg/kg q 4 
weeks if ≤ 30kg total body weight.  
 Day 1 of concurrent durvaRT treatment should start on a Monday, Tuesday or 
Wednesday. 
 
5.4.2 Adjuvant durvalumab 
 Post-concurrent durvaRT, single agent durvalumab, will be delivered every 4 weeks for a 
total period of up to 12 months (1500 mg Q 4 weeks if patients are >30kg OR 20mg/kg Q 
4 weeks if ≤ 30kg total body weight). 
 Adjuvant durvalumab treatment will be started 3-4 weeks post completion of durvaRT 
treatment.  


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 Subjects who have a dose interruption due to toxicity at any point in the first 12 months 
of treatment may resume treatment but the 12-month treatment period may not be 
extended. 
 Subjects will receive a maximum of 13 doses (or a 12-month treatment period, whichever 
occurs first) of Q4 week durvalumab during the entire course of adjuvant treatment.   
 
5.5 
Radiation Therapy  
Note: Intensity Modulated Radiation Therapy (IMRT) is required on this study. Central 
review of radiation therapy plans will not be prospectively performed.  
IMRT may be performed at the research institution or performed locally for patient 
convenience. Regardless, all facilities must deliver IMRT according to the specifications 
below. 
 
5.5.1 Dose Specifications:  
Radiotherapy will be started within 8 weeks of maximal TURBT on a Monday, Tuesday, or 
Wednesday. The overall schema is for whole bladder and involved lymph node treatment for 28 
daily fractions of 1.8 Gy per fraction (5 days per week) to 50.4 Gy, followed by a boost to the 
bladder tumor area with margin (partial sparing of bladder) using 1.8 Gy per fraction for an 
additional 8 daily fractions to a total dose of 64.8 Gy. During the bladder tumor area boost phase, 
involved lymph nodes may be treated to 54 Gy – 64.8 Gy at the discretion of the treating 
radiation oncologist if able to achieve acceptable normal tissue dose constraints. 
 
5.5.2 Technical factors:  
Photon IMRT with megavoltage equipment capable of delivering static intensity modulation 
with a multileaf collimator or dynamic intensity modulation using a multileaf collimator or 
tomotherapy is required. 6 – 10 MV energy photon beams should be used. VMAT is allowed. 
Protons are not allowed. 
 
5.5.3 Immobilization and Simulation: 
  
Immobilization 
Proper immobilization is required for this protocol but the specific method of immobilization is 
up to the discretion of the treating institution. Patient setup reproducibility must be achieved 
using appropriate clinical devices that might include customized torso cradles and/or leg 
immobilizers. 
 
Simulation Imaging 
Patients must be immobilized in the supine position. IV and/or PO contrast may be used to help 
delineate anatomy but are not required. The patient should void to empty the bladder 
immediately prior to simulation. 
 
CT scan thickness should be ≤ 3 mm through the region that contains the target volumes and the 
critical structures evaluated in Dose-Volume Histogram analysis. The CT scan should extend at 
least 4 cm above and below target volumes. Superior limit of the scan may be at the L1/2 
interspace and the inferior limit below the perineum. 
 


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5.5.4 Definition of Target Volumes and Margins:  
 
GTVp: The GTVp will include the bladder tumor bed as defined by imaging, cystoscopy, or 
fiducials if placed. 
 
CTVp: The CTVp will be a 10 mm expansion of GTVp. 
 
GTVn: The GTVn will include clinically involved regional lymph nodes. 
 
CTVn: The CTVn will be a 5 mm expansion of GTVn. 
 
CTV_5040: The CTV_5040 will represent the (whole empty bladder including GTVp) + 10 mm 
expansion and the CTVn if applicable. 
 
PTV_5040: The PTV_5040 will be a direct expansion of 7 mm beyond the CTV_5040. 
CTVp_6480: The CTVp_6480 represents the bladder tumor bed boost volume. 
 
PTVp_6480: The PTV_6480 will be a direct expansion of 7 mm beyond the CTV_6480. 
 
CTVn_boost: The CTVn_boost represents the CTVn, which will receive dose escalation beyond 
the initial 50.4 Gy at the discretion of the treating radiation oncologist (i.e. range between 54 – 
64.8 Gy). 
 
PTVn_boost: The PTVn_boost will be a direct expansion of 7 mm beyond the CTVn_boost. 
 
5.5.5 Critical Structures 
 
Bowel Space: Superiorly, the bowel space contour will start 3 cm above the superior extent of the 
CTV5040. Inferiorly the contour will be discontinued on the CT slice where no portion of small 
bowel or colon is visible. The contours will include the volume surrounding loops of bowel out 
to the edge of the peritoneum as bowel may occupy this space at any time during the course of 
treatment. Bowel space will include the small bowel and large bowel in one bowel bag contour. 
Attempts should be made to keep Bowel space V40Gy <50%, but V40Gy of 50 – 70% would be 
variation acceptable. 
 
Rectum: The rectum contour will include the rectum and anal canal and will be contoured on 
every slice from the rectosigmoid junction superiorly to the level of the ischial tuberosities 
inferiorly. Attempts should be made to keep Rectum V45Gy <80%, but V45Gy of 80 – 90% would 
be variation acceptable. 
 
5.5.6 Dose Prescription 
Normalization of Dose: The initial plan is normalized such that 97% of the PTV_5040 volume 
receives the prescription dose of 50.4 Gy. The bladder tumor boost plan is normalized such that 
97% of the PTVp_6480 volume receives the prescription dose of 64.8 Gy. If involved nodal 
boost is delivered beyond 50.4 Gy then that plan is normalized such that 97% of the PTVn 
volume receives the chosen prescription dose. 


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5.5.7 Daily Treatment Localization/Image Guided Radiation Therapy (IGRT) 
The patient should void to empty the bladder immediately prior to treatment. Daily IGRT images 
should be obtained to ensure proper alignment of the isocenter of the simulated fields. These 
IGRT images may include 1) conebeam CT (CBCT) with MV or kV x-ray; or 2) paired kV 2D 
images. 
 
5.6 
Pre-medication and Hydration 
Premedication and hydration prior to durvalumab will be provided according to institutional 
standards, per treating physician discretion. It is not essential to give any anti-nausea or anti-
allergic drug prior to durvalumab, but premedication such as ondansetron, diphenhydramine, etc. 
are allowed if clinically indicated. Steroids should not be given as a premedication.  
 
5.7 
Preparation of durvalumab doses for administration with an IV bag 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. The dose of durvalumab will be administered using an IV bag containing 0.9% (w/v) 
saline with a final durvalumab concentration ranging from 1 to 20 mg/mL, and delivered through 
an IV administration set with a 0.2- or 0.22-μm in-line filter. Remove a volume of IV solution 
from the IV bag equal to the calculated volume of durvalumab to be added to the IV bag prior to 
addition of durvalumab.  Next, the volume of durvalumab (e.g., 30.0 mL for 1500 mg of 
durvalumab) is added to the IV bag such that final concentration is within 1 to 20 mg/mL (IV 
bag volumes 100 to 1000 mL).  Mix the bag by gently inverting to ensure homogeneity of the 
dose in the bag. 
 
For patients weighing ≤30 kg total body weight, the baseline weight or the weight on day of 
dosing can be used to calculate each dose, as per institutional standard. However, if there is a 
≥10% change in weight from baseline, the day of dosing weight should be used. See dose 
calculation example in the Documents/ Info tab of the EDC. 
 
5.8 
Durvalumab Administration 
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 or 0.22-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.  
 
5.8.1 Monitoring of dose administration 
Subjects will be monitored before, during and after the infusion with assessment of vital signs at 
the times specified in the Schedule of Assessments. Subjects are monitored (pulse rate, blood 
pressure) every 30 minutes during the infusion period (including times where infusion rate is 
slowed or temporarily stopped). 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion.  For subjects with a ≤Grade 2 


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infusion-related reaction, subsequent infusions may be administered at 50% of the initial 
rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications 
per institutional standard may be administered at the discretion of the investigator.  If the 
infusion-related reaction is Grade 3 or higher in severity, study drug will be permanently 
discontinued and the subject will be followed up per protocol. The standard infusion time is one 
hour, however if there are interruptions during infusion, the total allowed time from infusion start 
to completion of infusion should not exceed 4 hours at room temperature. See also Section 10.4.  
 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis.  The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary. 
 
5.9 
Concomitant Medications 
 
5.9.1 Allowed Concomitant Medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed in Section 5.8.2. Premedication is not 
required prior to durvalumab but can be given per physician discretion 
 
For local recurrence T1 or CIS lesions in bladder detected by cystoscopy during adjuvant 
monotherapy with durvalumab, intravesical mitomycin C will be permitted if clinically 
necessary. 
 
5.9.2 Prohibited Concomitant Medications 
 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies. For 
local recurrence T1 or CIS lesions in bladder during adjuvant monotherapy with 
durvalumab, intravesical BCG is prohibited. However intravesical BCG is permitted post 
completion of adjuvant durvalumab.  
2. Any concurrent chemotherapy, biologic or hormonal therapy for cancer treatment. 
Concurrent use of hormones for noncancer-related conditions (e.g., insulin for diabetes 
and hormone replacement therapy) is acceptable.  NOTE: Local treatment of isolated 
lesions for palliative intent is acceptable by local surgery.  
3. Patient should not get any palliative RT during the study. If the treating physician 
deems palliative RT as clinical necessity then patient needs to come off the study.  
4. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted. A temporary period of 
steroids will be allowed for select indications, at the discretion of the sponsor-investigator 
(e.g., asthma, chronic obstructive pulmonary disease, radiation, nausea, etc. a temporary 


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course of steroid upto a maximum of 1mg/d for 7 days will be allowed). Topical steroids 
are not contraindicated.  
5. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the 
first dose, during treatment with durvalumab and for 30 days post discontinuation of 
durvalumab.  Inactivated vaccines, such as the injectable influenza vaccine, are 
permitted. 
 
Table. Rescue Medications 
Rescue/supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments (eg, acetaminophen or 
diphenhydramine) deemed necessary by the Investigator to 
provide adequate prophylactic or supportive care, except for those 
medications identified as “prohibited” as listed above 
To be administered as 
prescribed by the 
Investigator 
Best supportive care (including antibiotics, nutritional support, 
growth factor support (except during durvaRT), correction of 
metabolic disorders, optimal symptom control, and pain 
management [including palliative surgery, etc])
Should be used when 
necessary for all patients 
 
5.3.3    Restrictions during the study 
 
Contraception 
Females of childbearing potential who are sexually active with a non-sterilised male partner must 
use 2 methods of effective contraception from screening, and must agree to continue using such 
precautions for at least 90 days following the last infusion of durvalumab; cessation of birth 
control after this point should be discussed with the treating physician.  Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of birth control. 
 
 Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause). 
 Subjects must use 2 acceptable methods of effective contraception as described below. 
 Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see table below) from 
Day 1 and for 90 days after receipt of the final dose of investigational product. 
 
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 shot or 
injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Combined pill
Minipill 
Patch 
a 
This is also considered a hormonal method.


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Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab. 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 will be used to grade 
adverse events.  
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation as specified in Study Calendar & 
Evaluations.   
 
6.1 
Dose Delays/Dose Modifications 
 
During durvaRT: 
Treatment may be delayed ≤ 3 weeks from the expected date of the next treatment for any reason 
during durvaRT.  If treatment is delayed ≤ 3 weeks, subjects will proceed with the next cycle of 
treatment according to the tables below. If the treatment delay is due to toxicity from durvalumab 
alone, RT will continue as planned. However, grade 3 or 4 adverse events due to durvalumab 
that persist for more than 7 days should result in discontinuation from study treatment. 
 
If the dose of durvalumab is held without a delay in RT, then those doses will not be given at a 
later date. But if durvalumab and RT are both held for any reason, then the durvalumab can 
resume upon re-start of RT. 
 
During adjuvant durvalumab: 
Treatment delay of no more than 12 weeks is permitted during adjuvant durvalumab. This is to 
allow recovery from any adverse events or unexpected events such as need for repeat TURBT 
and intravesical mitomycin, etc. See also Appendix 5 for guidelines during COVID-19. 
 
Held or missed doses will be made up during adjuvant durvalumab.  
A new treatment cycle will only be initiated when all of the following conditions are met:  
 ANC ≥ 1,000× 109/L 
 Hb ≥8.0 g/dL (transfusion is allowed to reach Hb 8.0) 
 Platelets ≥ 75× 109/L 
 Non-hematologic treatment related toxicities have improved to ≤ Grade 2 or to the 
subject’s baseline values (except alopecia).  
 
If blood counts are below this threshold, blood work is to be repeated weekly until counts are at 
an acceptable level. If treatment is unable to restart within 3 weeks during durvaRT or within 12 
weeks during adjuvant durvalumab of the planned treatment date, the subject will be 


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permanently discontinued from study therapy.  
 
Please note that radiation-induced local side effects will be documented and treated by 
radiation oncology and medical oncology team according to local practice. Adjustments or 
discontinuation of radiation therapy will be made by radiation oncology. This is to avoid 
any unnecessary delay during RT for local side effects such as radiation proctitis or radiation 
dyspareunia etc. as these would be expected and, as a standard of care, RT is not usually delayed 
in these circumstances. The radiation related local toxicities will be managed per standard of 
care. However, radiation oncology should promptly notify medical oncology and discuss 
any unexpected adverse events or potential inflammatory or immune-mediated adverse 
events. The final radiation treatment records will be sent to medical oncology for review of 
clinical and safety-related data. 
 
6.2 
Durvalumab  
For adverse events (AEs) that are considered at least partly due to administration of durvalumab, 
the following guidance will be applied: 
 Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
 If the symptoms promptly resolve with supportive care, continue durvalumab along with 
appropriate continuing supportive care according to Appendices 1-4. 
 All dose delays 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 will be 
managed based on toxicities observed (see Appendices 1-4).  Dose delays during phase 1 should 
follow rules listed in DLT section, 5.3.2 and 5.3.3. 
 
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 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
Appendices 1-4.   
 
In addition, management guidelines for adverse events of special interest (AESIs) are 
detailed in Section 5. All toxicities will be graded according to NCI CTCAE v4. Please refer 
to dose modification guidelines listed in appendices 1-4 for durvalumab-related toxicities. 
 
Hematological Toxicity and Recommendation for Treatment Delay during durvaRT:  


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Description  
Treatment Delay 
Any other grade 3 non-hematologic toxicity  
Up to 3 week delay  
Any other grade 4 non-hematologic toxicity  
Discontinue treatment  
Neutrophils 990-500 cells/mm3 
Up to 3 week delay 
Neutrophils <500 cells/mm3 
Up to 3 week delay 
Febrile Neutropenia (Fever+ANC <500cells/mm3) 
Discontinue treatment 
Platelets 50,000 /mm3 to 75,000/mm3
Up to 3 week delay  
Platelets  >25,000 but <50,000/mm3 
Up to 3 week delay 
Platelets <25,000/mm3 
Discontinue treatment 
Any other grade 4 hematologic toxicity 
Discontinue treatment  
 
Recommendation for Treatment Delay during Adjuvant Durvalumab as monotherapy: 
Please follow toxicity guidelines, as durvalumab has no direct bone marrow toxicity.  
 
If treatment delay necessities >3 weeks during concurrent durvaRT, treatment is stopped and the 
subject is discontinued from the study. 
 
If treatment delay necessitates a period longer than 12 weeks during adjuvant durvalumab, 
treatment is stopped and the subject is discontinued from the study. See also Appendix 5 for 
guidelines during COVID-19. 
 
6.3 
Radiation Treatment Interruption  
If a grade 3 hematologic toxicity (ANC, platelets) develops during immunoradiotherapy, all 
treatment should be discontinued for a minimum of one week. Treatment may be resumed when 
the hematologic toxicity resolves to < grade 2. If these laboratory values have not been reached 
after a one-week delay, they should be checked weekly until they become acceptable. If after 3 
weeks the blood counts have not recovered, all protocol treatment should be discontinued and the 
patients should be treated on an individual basis. Please refer to table in section 6.4 for 
recommendations for hematological toxicities during concurrent durvaRT 
 
For a grade 3 acute colitis, or any immune related toxicity during any week, treatment should be 
delayed until the toxicity subsides to the < grade 2 level. Use of anti-diarrheal agents, such as 
loperamide or diphenoxylate/atropine, is strongly encouraged at an early point in treatment to 
avoid worsening of treatment-related diarrhea. 
 
Radiation-induced toxicities such as radiation cystitis, radiation- proctitis, radiation 
dyspareunia or any other grade 3 infield (radiation-related) will be documented and 
treated by radiation oncology according to local practice. Treatment interruption or 
discontinuation will be decided by the treating radiation oncologist. Radiation to the bladder is 
associated with significant local toxicity but current standard of care is to continue RT while 
conservatively managing local toxicities. Similar toxicity is expected during durvaRT, hence 
treatment should be continued per standard of care. However, radiation oncology should 
promptly notify medical oncology and discuss any unexpected adverse events or potential 


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inflammatory or immune-mediated adverse events. The final radiation treatment records will 
be sent to medical oncology for review of clinical and safety-related data. 
 
Potential toxicities associated with radiation therapy to the pelvis include loss of pubic hair, 
cutaneous erythema in the treated area, increased urinary frequency (which could be permanent), 
fatigue, nausea, vomiting, rectal irritation, dyspareunia, ovarian failure in women, and sterility. 
Less likely but potential serious toxicities include weight loss, rectal ulcers, hematochezia, bowel 
obstruction, bowel perforation, ureteral obstruction, and fistula formation. Bleeding from the 
mucosal surface is potentially both an acute and chronic complication. 
 
6.4 
 Toxicity management guidelines for combination treatment regimen 
In addition to the individual toxicity management guidelines for durvalumab and RT described 
above, Table 1 outlines what actions are recommended for the management of any potential 
overlapping toxicities that may occur following treatment with this combination (e.g., which agent 
should be modified first, etc). 
 
Table 1: Toxicity management for durvalumab and radiation therapy during concurrent 
durvaRT phase 
Toxicity 
Action for durvalumab 
Action for Radiation Therapy 
Any grade 1 toxicity  
 
Grade 2, hematological toxicity 
(ANC, platelet) 
Continue treatment 
 
Continue treatment 
Continue treatment 
 
Continue treatment 
Grade 3 hematological toxicity 
(ANC or platelets) 
Hold till AE ≤grade 2 
If these laboratory values have not 
been reached after a one-week 
delay, they should be checked 
weekly until they become 
acceptable. If after 3 weeks the 
blood counts have not recovered, 
all protocol treatment should be 
discontinued and the patients 
should be treated on an individual 
basis. 
Hold till AE ≤grade 2 
If these laboratory values have not been 
reached after a one-week delay, they 
should be checked weekly until they 
become acceptable. If after 3 weeks the 
blood counts have not recovered, all 
protocol treatment should be 
discontinued and the patients should be 
treated on an individual basis. 
Grade 2,3 acute colitis, or 
immune related side-effect 
from durvalumab 
Treatment should be delayed until 
the toxicity subsides to grade 1. 
Refer to appendices 1-4. 
Assess weekly and if after 3 
weeks, the toxicities have not 
recovered to grade 1 or less, all 
protocol treatment needs to be 
discontinued
Treatment should be continued if the 
side-effect is thought to be not related to 
RT. Please note colitis can be seen with 
RT too, hence if this occurs treatment 
should be delayed until it is grade 1. 
Assess weekly and if after 3 weeks it 
does not recover to grade 2, discontinue 
treatment on study. 
Any other grade 1-3 infield 
(radiation-related) toxicity 
during any week such as but 
not limited to-skin toxicity, 
radiation proctitis, radiation 
cystitis, radiation dyspareunia. 
Treatment should be continued if 
the side-effect is not related to 
durvalumab 
Treatment should be delayed as 
medically necessary per treating 
radiation oncologist.  
Radiation to the bladder is associated 
with significant local toxicity but 
current standard of care is to continue 
RT while conservatively managing local 
toxicities. Similar toxicity is expected 
during durvaRT, hence treatment should 
be continued per standard of care.


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6.5 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in section 6.1, a 
subject will also be discontinued from protocol therapy and followed up per protocol under the 
circumstances outlined below. The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF). 
 Documented disease progression per protocol.  
 The treating physician thinks a change of therapy would be in the best interest of the subject 
 Grade 3 or 4 adverse events that persist for more than 7 days 
 The subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), the 
subject should be asked if he or she may still be contacted for further scheduled study 
assessments. The outcome of that discussion should be documented in both the medical 
records and in the eCRF. 
 A female subject becomes pregnant  
 If protocol therapy is interrupted for >3 weeks during concurrent durvaRT or >12 weeks 
during adjuvant durvalumab as monotherapy. See also Appendix 5 for guidelines during 
COVID-19.  
 
Permanent discontinuation of durvalumab 
A subject will not receive any further durvalumab if any of the following occur: 
 Withdrawal of consent or lost to follow-up. 
 Adverse event that, in the opinion of the treating physician, contraindicates further 
dosing. 
 Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk. 
 Pregnancy or intent to become pregnant. 
 Dose-limiting toxicity as above. 
 Grade ≥ 3 infusion reaction. 
 Subject noncompliance that, in the opinion of the treating physician or sponsor-
investigator, warrants withdrawal; eg, refusal to adhere to scheduled visits. 
 Initiation of alternative anticancer therapy including another investigational agent. 
 Criteria met for discontinuation of treatment as described in the protocol.  
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety according to the study calendar, including the collection of any protocol-
specified blood specimens, unless consent is withdrawn or the subject is lost to follow-up.  All 
subjects will be followed for survival.   
 
Withdrawal of consent 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation.  


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7. 
TREATMENT CALENDAR & EVALUATIONS 
 
Screen
DurvaRT1 (±3) 
Post durvaRT
Adjuvant Durvalumab2 
-28 d
W1
W3
W5
W7 
W10-11 (±7)
Q4W (±5)
Q12W (±7)
REQUIRED ASSESSMENTS 
 
Informed Consent; Medical History5 
X
 
Diagnosis and Staging6 
X
 
Physical Exam7 and ECOG PS8 
X
X
PhI
X
X 
X
Vital signs9 
X
5x 
3x
X 
3x
Weight, height (screen only) 
X
X
X
 
X
ECG10 
X
X (x2)
 
C1D1 only
AEs and AESIs7 
X
X
PhI
X
X 
X
Concomitant Medications11 
X
X
PhI
X
X 
X
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count with diff (CBC)12 
X
Weekly12,13 
X
Comprehensive Metabolic Profile (CMP)14
X
X13
X
X 
X
GGT (baseline), Mg, Phos, Uric Acid, LDH
X
X13
X
X 
X
Phase Ib only: liver enzymes15 
PhI only: Weekly  
TSH (free T3, free T4 if TSH abnormal)16
X
X13
X 
X
Pregnancy test (serum or urine) WOCBP17
-3 d
 
Urinalysis18 
X
X
X
X 
X
Hepatitis serologies; HIV testing19 
X
 
Coagulation panel20 
X
 
DISEASE ASSESSMENT 
 
Cystoscopy (TURBT, if applicable)21 
-8 wks
 
X
X
CT of chest, abdomen and pelvis22 
X
 
X
X
TREATMENT EXPOSURE 
 
Radiation Therapy (36 fractions) 
daily Mon-Fri1
Durvalumab 
X
X
 
X
CORRELATIVE STUDIES (SPECIMEN COLLECTION)
 
Archival tumor tissue for PD-L1, if available23 
X
 
Fresh tumor biopsy24 
X
 
X
Urine sample for cell free DNA23 
X
 
Blood PBMCs and inflammatory cytokines 25 
X
 
C1D1 only
Blood for somatic baseline26 
X
 
Prior NGS results, if performed27 
X
 
BANKING SAMPLES (SPECIMEN COLLECTION)
 
Serum and Plasma29 
X
 
Unstained Slides28 (if available) 
X
 


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FOLLOW UP CALENDAR & EVALUATIONS 
 
Safety 
follow up3 
(±7)
Long-term follow up4  
for a total of 3 years from the start of adjuvant treatment 
(±14) 
30 days 
post
3-month 
6-month 
9-month 
12-month
18-month
24-month
36-month
REQUIRED ASSESSMENTS 
 
Physical Exam7 and ECOG PS8 
X
X*
X*
X* 
X*
X*
X*
X*
Vital signs9 
X
X*
X*
 
ECG10 
X
 
AEs and AESIs7 
X
X*
X*
 
Concomitant Medications11 
X
X*
X*
 
LABORATORY ASSESSMENTS 
 
Complete Blood Count with diff (CBC)12 
X
X
 
Comprehensive Metabolic Profile (CMP)14
X
X
 
GGT (baseline), Mg, Phos, Uric Acid, LDH 
X
X
 
TSH (free T3, free T4 if TSH abnormal)16 
X
 
DISEASE ASSESSMENT 
 
Cystoscopy (TURBT, if applicable)21 
 
CT of chest, abdomen and pelvis22 
X
X4*
X4*
X4* 
X4*
X4*
X4*
X4*
CORRELATIVE STUDIES (SPECIMEN COLLECTION)
 
NGS results, if performed27 
@ PD
Blood for PBMCs and inflammatory 
cytokines 25 
X 
 
 
 
 
 
 
 
BANKING SAMPLES (SPECIMEN COLLECTION)
 
Serum and Plasma29 
X
 
FOLLOW-UP 
 
Survival status, subsequent therapy 
X
X
X 
X
X
X
X
* Assessments for subjects who have discontinued durvalumab without disease progression. 
 
 


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Calendar Footnotes: (See also Appendix 5 for guidelines during COVID-19.) 
1. DurvaRT: durvalumab will be started on Day 1 of Week 1; RT will be started on Day 1 or 2 of Week 1. RT will be 64.8 Gy combined with 
Q4 week durvalumab on weeks 1 and 5. RT may be performed at the research institution or local institution for patient convenience. 
2. Adjuvant Durvalumab: Single agent durvalumab will be given every 4 weeks for up to 12 months (13 doses) during adjuvant durvalumab. 
Adjuvant durvalumab will be started 3-4 weeks post completion of durvaRT. 
3. Safety follow up visit: The safety follow-up visit should occur when subjects permanently stop study treatment for whatever reason (toxicity, 
progression, or at discretion of site investigator) and should be performed 30 days (±7 days) after the last dose of treatment. Subjects who have 
an ongoing ≥ grade 2 or serious AE (SAE) at this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, deemed 
clinically insignificant, and/or until a new anti-cancer treatment starts, whichever is earlier. 
4. Long-term follow up: Long-term follow up will occur in all subjects for a total of 3 years from the start of adjuvant treatment. If a subject did 
not begin adjuvant treatment, long-term follow up will start 4 weeks after the last dose of radiation or from the time of first imaging for 
evaluation of response whichever is earliest. Subjects who discontinue treatment for any reason without documented disease progression, prior 
to completion of 12 month period of adjuvant therapy, will be followed every 12 weeks (±4 wks) for year 1, every 6 months (±4 weeks) for 
year 2, and annually for year 3 (or per local guidelines) or until confirmed PD for a total of 3 years from the start of adjuvant treatment. Once 
disease progression is documented, subjects will enter a survival follow up period every 3 months for 3 years for a total of 3 years from the 
start of adjuvant treatment. For subjects who achieve disease control after 12 months of adjuvant treatment or discontinue due to toxicity or 
symptomatic deterioration, tumor assessments should be performed every 3 months post completion of adjuvant therapy for 12 months, and 
thereafter every 6-months for the remainder of the following year or according to local practice. E.g., post completion of 12 months of 
adjuvant therapy- follow up for imaging Q3 months x 1 year then Q6 months for the following year. 
5. Medical History: to include demographics, tobacco and alcohol use, trial awareness question, prior treatments, and surgical history. 
6. Diagnosis and staging: to include pathology report and Tumor Node Metastasis (TNM) staging 
7. Physical exam and AE assessment: During durvaRT: with radiation oncology as per local practice; W1, W3, W5 and W7 by medical 
oncology during DLT assessment in phase Ib only; W1, W5 and W7 by medical oncology in phase II. During adjuvant durvalumab 
monotherapy: every 4 weeks with med onc; with rad onc as per local practice. 
8. ECOG PS: screen, Day 1, and at each visit by medical oncology. 
9. Vital signs: Non-durvalumab visits: to include temperature, blood pressure, pulse rate, respiratory rate. Durvalumab visits: Blood pressure and 
pulse will be measured before, during, and after the infusion at the following times (based on a 60-minute infusion): At the beginning of the 
infusion (within 1 hr prior to start); at 30 minutes during the infusion (±5 minutes); at the end of the infusion (at 60 minutes ±5 minutes); 
During the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the start of the infusion) 
(±5 minutes) for the first infusion only and then for subsequent infusions as clinically indicated. If the infusion takes longer than 60 minutes, 
blood pressure and pulse measurements should be collected every 30 minutes (±5 minutes) and as described above or more frequently if 
clinically indicated.  
10. ECG: An ECG is required during screening, pre and post study treatment on Week 1 Day 1 of concurrent durvaRT, at the start of adjuvant 
durvalumab, at the safety follow up visit, as well as at any other time point when clinically indicated. All ECGs will be single tracings. Week 1 
Day 1 ECGs will be performed within an hour prior to start of infusion and at least one time point 0 to 3 hours after the infusion. 
11. Concomitant medications: assessed at each med onc physical exam visit. 
12. CBC: to be drawn weekly during durvaRT and q4 weeks during adjuvant durvalumab. 
13. If screening (baseline) labs were performed within 7 days of D1 of treatment, these do not need to be repeated. 


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14. CMP: to include albumin, alk phos, ALT, AST, amylase, bicarbonate, calcium, chloride, creatinine, Gamma glutamyltransferase (GGT; 
baseline and if clinically indicated); glucose, lactate dehydrogenase (LDH), lipase, magnesium, potassium, sodium, total bili, total protein, 
urea/BUN, uric acid. CMP to be drawn prior to each durvalumab infusion (Weeks 1, 5, 7 during durvaRT; Q4 weeks during adjuvant 
durvalumab). 
15. Liver enzyme panel, Phase Ib only: To include AST, ALT, alk phos, bilirubin. To be drawn weekly during phase 1 part of durvaRT only (if 
not already included in the CMP). 
16. Thyroid stimulating hormone: Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is 
clinical suspicion of an adverse event related to the endocrine system. 
17. Pregnancy testing: Urine hCG or serum βhCG in women of childbearing potential (WOCBP). Perform within 3 days of registration and 
repeat during Treatment Period as clinically indicated.  
18. Urinalysis: performed at Screening, pre-dose W1 and W5 of durvaRT, W7, and q4 weeks during adjuvant durvalumab. 
19. Hepatitis serologies and HIV: if applicable, per physician discretion. Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody, 
HIV antibody. 
20. Coagulation panel: to include prothrombin time (PT), aPTT and INR. To be performed at screening and as clinically indicated. 
21. Cystoscopy (maximum TURBT if applicable): Baseline: Maximum TURBT within 8 weeks prior to starting durvaRT. Another cystoscopy 
will be done between Weeks 9-10 (around 2-3 weeks post completion of durvaRT). During adjuvant durvalumab: Every 12 weeks. TURBT if 
indicated. 
22. Disease imaging: Baseline CT scans (IV contrast preferred) of chest and abdomen and pelvis are required within 28 days of study registration. 
Obtain urogram at baseline if possible. CT scans to be performed at screening and 2-3 weeks post completion of all durvaRT. Timing of 
adjuvant durvalumab CT scans is every 12 weeks (± 7 days); timing of follow up CT scans is every 12 weeks (± 14 days). At screening, CT 
scans are preferred but MRI of abdomen and pelvis are acceptable. Follow up imaging of chest: CT chest preferred but CXR is allowed. The 
study requires scans to confirm progression for patients who are deemed clinically stable by the treating Investigator. The confirmatory scan is 
acquired preferably at the next regularly scheduled imaging visit and no earlier than 4 weeks after the prior assessment of PD. CR, PR, SD 
need to be confirmed with another scan on next clinic visit and no sooner than 4 weeks.  
Correlative Studies: See CLM for collection, processing, labelling and shipping instructions. 
23. Please note that any tissue specimen remaining after PD-L1 testing at baseline and post durvaRT will be used to determine mutational 
sequencing of tumor. Between 15 FFPE slides or tissue block (preferred) are requested (minimum of 10 slides x 10 micron (μm) thick and 5 
slides x 4 μm thick). If 15 slides are not available, the investigator must discuss this with the sponsor-investigator on a case by case basis. 
Similarly, for urine sample at baseline, we will use leftover sample to perform mutational sequencing.  
24. Obtain fresh tumor biopsy for PD-L1 assay with cystoscopy, if applicable (pts undergoing TURBT).  
25. Flow cytometry collection of whole blood for PBMCs to determine PD-1 on T cells. Plasma will be collected. Inflammatory cytokines such as 
IFN-γ concentration in plasma will be assessed by Bead-based immunoassays. In addition, intracellular IFN-γ release by T cells will be 
assessed by flow cytometry. 
26. Submission of whole blood for somatic baseline is to be collected at Pre-Treatment Cycle 1 Day 1.  
27. Prior NGS results: enter into EDC if performed as per standard of care prior to study and/or at progression. 
28. Banking Studies: See CLM for collection, processing, labeling and shipping instructions. Submission of unstained slides for banking from an 
archived FFPE tumor block (if available). 
29. Submission of serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the Safety Follow up visit. 
 


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7.1 
Screening Evaluations 
 
7.1.1 Within 28 days prior to registration for protocol therapy 
Screening procedures will be performed up to 28 days before registration, unless otherwise 
specified.  All subjects must sign the IRB-approved ICF before any study-specific screening 
procedures are performed.  After signing the ICF, completing all screening procedures, and being 
deemed eligible for entry, subjects will be enrolled in the study.  Procedures that are performed 
prior to the signing of the ICF and are considered standard of care may be used as screening 
assessments if they fall within the 28-day screening window. 
 
The following procedures will be performed during the Screening Visit: 
 Informed Consent 
 Review of eligibility criteria 
 Medical history to include demographics, tobacco and alcohol use, prior treatments, and 
surgical history  
 Diagnosis and staging to include pathology report and Tumor Node Metastasis (TNM) 
staging 
 Complete physical exam. Patient must be seen by medical oncology prior to starting Day 
1 of treatment with durvaRT. Radiation therapy planning will be performed according to 
institutional standards. 
 ECOG Performance Status 
 Vitals signs to include temperature, blood pressure, pulse rate, respiratory rate 
 Weight and height  
 12-lead ECG. A 12-lead ECG should be obtained after the subject has been resting in a 
supine position for at least 5 minutes.  
 Baseline signs and symptoms 
 Concomitant medications 
 Complete blood count with differential (CBC): to include basophils, eosinophils, 
hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, mean corpuscular volume, monocytes, neutrophils, platelet 
count, red blood cell count, total white cell count.  
 Comprehensive metabolic panel (CMP): to include albumin, alkaline phosphatase, 
alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, calcium, 
chloride, creatinine, gamma glutamyl transferase (GGT), glucose, lactate dehydrogenase, 
lipase, 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.  
 Thyroid stimulating hormone. Free T3 and free T4 will only be measured if TSH is 
abnormal.  
 [Within 3 days of registration] Urine hCG or serum βhCG pregnancy test for women of 
childbearing potential (WOCP)  
 Urinalysis: to include bilirubin, blood, glucose, ketones, pH, protein, specific gravity, 
color and appearance. Microscopy should be used as appropriate to investigate white 
blood cells and use the high power field for red blood cells.  


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 Hepatitis serologies and HIV: if applicable, per physician discretion. Hepatitis A 
antibody, hepatitis B surface antigen, hepatitis C antibody, HIV antibody. 
 Coagulation panel: to include prothrombin time (PT), aPTT and INR. 
 Cystoscopy with maximal TURBT within 8 weeks of study registration.  
 CT chest, abdomen and pelvis with contrast (contrast is preferred but patients with 
contraindication for contrast may have non-contrast imaging); urogram at baseline if 
possible; MRI abdomen and pelvis are acceptable but CT is preferred. 
Correlative studies: 
 Tumor biopsy specimen from recent TURBT (preferred) or LN core biopsy within 8 
weeks prior to enrollment. Tissue block is preferred, if available. An alternative is to 
submit at least 15 FFPE slides with tumor specimen (a minimum of 10 slides x 10 μm 
thick and 5 slides x 4 μm thick). If 15 slides are not available, the investigator must 
discuss this with the sponsor-investigator on a case by case basis. 
 Prior NGS results: enter into EDC if performed as per standard of care prior to study 
 
7.2 
On Treatment Evaluations 
 
Each cycle of durvalumab during concurrent durvaRT= 28 days or 4 weeks; Delay of 3 weeks is 
permitted during the concurrent durvaRT phase for any unexpected/adverse events/need for a 
repeat TURBT. Please see details in dose delay section.   
 
Each cycle of durvalumab as monotherapy=28 days or 4 weeks. A maximum 12-week delay is 
permitted between cycles due to a treatment related adverse event or need to repeat cystoscopy 
and TURBT.   
 
7.2.1 Concurrent durvaRT 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments.  Screening procedures performed within 7 days of Cycle 1 Day 1 (C1D1) do not 
need to be repeated on C1D1. 
 
Week 1 Day 1 of concurrent durvaRT- both phase Ib and II 
 Physical exam and ECOG PS 
 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 (within 1 hour prior to start) 
2. at 30 minutes after the start of infusion (± 5 minutes),  
3. at the end of infusion (at 60 minutes ± 5 minutes) 
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. 
 Weight 


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 Single tracing 12-lead ECGs within an hour prior to start of infusion and at least one time 
point 0 to 3 hours after the infusion. ECGs will be obtained after the subject has been resting 
in a supine position for at least 5 minutes. 
 Adverse events; concomitant medications 
 CBC with differential: Weekly x 7 weeks during durvaRT. If performed locally, results must 
be forwarded to medical oncology. 
 CMP including magnesium, phosphorus, uric acid and LDH 
 Thyroid stimulating hormone. Free T3 and free T4 will only be measured if TSH is 
abnormal. 
 Urinalysis 
 Durvalumab infusion: prior to RT is preferred but not mandatory.   
 Radiation therapy: start on a Monday, Tuesday, or Wednesday; after durvalumab is 
preferred. RT may begin on Day 1 or Day 2. 
 Correlative and Banking samples. See Correlative Laboratory Manual for specific 
instructions.  
 
Phase Ib subjects only: Weekly x 7 weeks (± 3 days):  
 Liver enzymes –ALT, AST, alkaline phosphatase, bilirubin 
 
Phase Ib subjects only: Week 3 (± 3 days) during durvaRT:  
 Vital signs: to include temperature, blood pressure, pulse rate, respiratory rate 
 Physical exam and ECOG PS 
 Assess adverse events (AE) and adverse events of special interest (AESI) by medical 
oncology 
 Concominant medications 
 
Week 5 (prior to the infusion, ± 3 days)- both phase Ib and II: 
 Physical exam; ECOG PS 
 Vital signs: blood pressure and pulse rate will be measured before, during and after the 
infusion. 1-hour post-infusion vitals only if clinically indicated. See Week 1 Day 1 schedule 
for time points.  
 Weight 
 Assess adverse events (AE) and adverse events of special interest (AESI) by medical 
oncology 
 Concomitant medications 
 CBC with differential: Weekly x 7 weeks during durvaRT. If performed locally, results must 
be forwarded to medical oncology.  
 CMP including magnesium, phosphorus, uric acid and LDH 
 Urinalysis 
 Durvalumab infusion 
 Radiation therapy (daily M-F) 
 
 
 


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Week 7 (± 3 days)- both phase Ib and II:  
 Physical exam and ECOG PS 
 Vital signs: to include temperature, blood pressure, pulse rate, respiratory rate 
 Assess adverse events (AE) and adverse events of special interest (AESI) by medical 
oncology 
 Concominant medications 
 CBC with differential  
 CMP including magnesium, phosphorus, uric acid and LDH 
 Urinalysis 
 
Please note that more frequent follow-ups can be done as clinically indicated by the treating 
physicians.  
 
Weeks 10-11: 2-3 weeks post completion of durvaRT (±7 days)- both phase Ib and II: 
 Cystoscopy evaluation 
o If sufficient tissue is available, obtain fresh tumor biopsy for PD-L1 assay with 
cystoscopy (pts undergoing TURBT). See Correlative Laboratory Manual for specific 
instructions. 
 Follow up disease imaging 
 
7.2.2 Adjuvant durvalumab as monotherapy 
See also Appendix 5 for guidelines during COVID-19. 
 
C1D1 of adjuvant monotherapy with durvalumab (within 4 weeks post durvaRT [±5 days]) 
 Physical exam, ECOG PS  
 Vital signs blood pressure and pulse rate will be measured before, during and after the 
infusion. 1-hour post-infusion vitals only if clinically indicated. See Week 1 Day 1 schedule 
for time points. 
 Weight  
 ECG-12 lead 
 Assess AEs and AESIs by medical oncology 
 Concomitant medications 
 CBC with differential 
 CMP including magnesium, phosphorus, uric acid and LDH 
 Thyroid stimulating hormone. Free T3 and free T4 will only be measured if TSH is 
abnormal. 
 Urinalysis 
 Durvalumab infusion 
 Correlative samples. See Correlative Laboratory Manual for specific instructions.  
 
The following will be performed on day 1 of subsequent cycles of adjuvant monotherapy 
with durvalumab (Q4 weeks [± 5 days]): 
 Physical exam, weight 
 Vital signs 
 ECOG PS 


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 CBC with differential 
 CMP including magnesium, phosphorus, uric acid and LDH 
 Assess AEs and AESIs by medical oncology 
 Concomitant medications 
 Durvalumab 
 
Every 12 weeks while on treatment with adjuvant durvalumab [± 7 days]: 
 Imaging for evaluation of response *** 
 Follow up by radiation oncology according to local standard of care 
 Cystoscopy  
***Please note:  CT scans, preferably with IV contrast, to be performed during screening (for 
baseline) and 2-3 weeks post completion of entire durvaRT (Week 10-11). Timing of on-
treatment (follow-up during adjuvant durvalumab) CT scans is every 12 weeks (± 1 week) until 
PD or off-study. The study requires a confirmation of progression scan for patients who are 
deemed clinically stable by the Investigator, then the confirmatory scan is acquired preferably at 
the next regularly scheduled imaging visit and no earlier than 4 weeks after the prior assessment 
of PD. MRI of abdomen and pelvis are acceptable instead of CT but CT scans are preferred. 
Follow up imaging of chest- CT chest preferred but CXR is allowed if CT chest not possible. 
 
Please follow study calendar for schedules of cystoscopy and imaging, clinic visits etc.  
 
7.3 
Safety Follow-up Evaluations at End of Treatment 
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.   
 
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For subjects who discontinue durvalumab prior to 12 months, end of treatment is considered the 
last visit where the decision is made to discontinue treatment. Repeat disease assessment is not 
required if performed within 28 days prior to the end of treatment visit.  
 
The following will be performed 30 days (± 7) after the last dose of study drug: 
 Physical exam, weight 
 Vital signs 
 ECOG PS 
 ECG-12 lead 
 CBC with differential 
 CMP including magnesium, phosphorus, uric acid and LDH 
 Assess AEs and AESIs by medical oncology 
 Concomitant medications 
 Correlative and Banking samples. See Correlative Laboratory Manual for specific 
instructions.  
o Prior NGS results: enter into EDC if performed as per standard of care at progression. 
 


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7.4 
Long Term Follow-up Evaluations (±14 days) 
All subjects will be followed for a total of 3 years from the start of adjuvant treatment. If a 
subject did not begin adjuvant treatment, long-term follow up will start 4 weeks after the last 
dose of radiation or from the time of first imaging for evaluation of response whichever is 
earliest. Subjects who discontinue treatment for any reason without documented disease 
progression prior to completion of 12 month period of adjuvant therapy, will be followed every 
12 weeks (±4 wks) for 1 year, every 6 months (±4 wks) for year 2, and annually for year 3 (or 
per local guidelines) or until confirmed PD for a total of 3 years from the start of adjuvant 
treatment (see Follow Up Study Calendar).  
 
Once disease progression is documented, subjects will enter a survival follow up period and will 
be followed every 3 months for a total of 3 years from the start of adjuvant treatment.  Follow up 
may be accomplished via clinic visit, or phone call. See Follow Up Study Calendar.  
 
7.5 
Description of study procedures 
 
7.5.1 Urologic Evaluation:   
 The treating urologist in all patients will perform an initial maximal TURBT no more 
than 8 weeks prior to initiation of therapy.  The goal of the initial resection will be 
maximal reduction of tumor volume and confirmation of unresectable status where 
applicable.  Photographic imaging will be performed to provide a record of baseline local 
disease.  
 
Follow up cystoscopies: When appropriate, bladder biopsy will be performed to 
document the presence or absence of CIS. Photographic imaging will be performed to 
document progression or lack thereof. Any suspected tumor progression will trigger a 
brief cessation of therapy to allow for TURBT with repeat maximal resection and 
pathologic confirmation of viable tumor.  Confirmed disease progression, defined as an 
increase in volume of a three-dimensional, viable, histologically confirmed cancer will be 
recorded as PD.    
 
 The post-durvaRT cystoscopic assessment will be performed approximately 2-3 weeks 
(±7 days) following the completion of 36 fractions of radiotherapy.  Flexible cystoscopy 
is optional. At this time, if a CR is suspected, confirmatory directed and random biopsies 
will be performed to rule out residual CIS.  In the event that CIS is the only finding, the 
patient will be deemed a CR but patient may be offered appropriate resection and 
intravesical mitomycin C therapy for CIS. Intravesical BCG is not allowed for this study. 
Patient will need to come off the study should patient decide to use BCG therapy per 
discussion by urologist. However, intravesical BCG is permitted after completion of 
adjuvant durvalumab.  
 
It should be noted that the use of cytology and FISH to determine presence of disease within the 
bladder is discouraged due to the potential confounding effects of the therapy on cytologic 
findings. 
 


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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
8.1 
Source and Timing of Biospecimen Collections 
Our correlative tests will include research testing on peripheral blood sample and on available 
tissue from TURBTs or biopsy of lymph node. TURBT specimens are preferred. We will also 
be collecting urine for further testing. The timings of collection of biospecimens are detailed in 
the study calendar.  
8.2 
PD-L1 Testing in tissue 
PD-L1 testing will be performed utilizing the Ventana SP263 assay.  Testing will be restricted to 
the Ventana SP263 assay and will be performed in accordance with the package insert on the 
Ventana Benchmark platform (Ultra or XT).   
 
For this study, PD-L1 biomarker will be used for exploring its predictive and prognostic 
implications. It will not be used for clinical decision-making. Please see the study calendar for 
details of time period for collection of tissue for PD-L1 testing. In addition, we will also be 
testing for PD-1 and FOXP3. 
 
Immunohistochemistry (IHC) will be performed as previously reported [41], and all IHC will be 
assessed by clinical pathologists through the use of the Allred system, which consists of the 
summation of IHC intensity and distribution of immunoreactivity.  Correlations amongst IHC 
scores for PD1, PDL1 and FOXP3, and between the extent of positive staining and tumor stage 
will be assessed using Spearman rank coefficients.  The extended Mantel-Haenszel test will be 
used to assess correlations between IHC scores after adjusting for tumor stage.  The association 
between IHC score and response to durvalumab (DCR, PFS, OS) will be tested via the 
application of Mann-Whitney U test following dichotomization at the mean. For progression-free 
survival (recurrence) analysis, univariate analyses will be performed using log rank tests and 
visualized using Kaplan-Meier survival curves.  Variables associated with adverse prognosis 
based on previous studies and variables with a P <0.10 on univariate analysis will also be 
included in a multivariate analysis using a Cox proportional hazards model if needed. 
 
Sample collection for PD-L1 testing 
 The preferred tumor sample for the determination of a patient’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy.  Samples taken at 
this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant.   
 In our study, baseline archival sample of tissue by TURBT or LN within 8 weeks of 
treatment is acceptable for PD-L1 testing.  
 Samples should have been collected via a core needle of 18 gauges or larger or be collected 
per institutional guidelines.  Where institutional practice uses a smaller gauge needle, 
samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) to allow for 
adequate PD-L1 immunohistochemistry analyses.   
 When the collection of a new sample is not clinically appropriate, archival samples may be 
utilized. Preferred archival sample is a specimen collected within 8 weeks from the start of 
treatment.  When archival samples are used to assess PD-L1 status, the age of the sample / 
date of collection should be captured.   


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 Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin.  
Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for PD-
L1 analysis.   
 If sufficient tissue is available at the post durvaRT cystoscopy, obtain fresh tumor biopsy 
for PD-L1 assay (pts undergoing TURBT). Sample collection will follow the guidelines 
described above and below.  
 
Sample data collection for PD-L1 testing 
The following fields of data should be collected from the site/institution collecting and if, 
indicated shipping of the samples:   
 Patient identifier (ecode or unique identifier) 
 Specimen identifier (written on the specimen) 
 Site identifier 
 Specimen collection date 
 Type of specimen submitted 
 Quantity of specimen 
 Date of sectioning 
 Archival of fresh tumor 
 Tumor type 
 Primary tumor location 
 Metastatic tumor location (if applicable) 
 Fixative 
 
The following data fields should be assessed at the PD-L1 testing laboratory: 
 Are the negative and positive controls stained correctly? 
 Is the H&E material acceptable? 
 Is morphology acceptable? 
 Total percent positivity of PD-L1 in tumor cells 
 PD-L1 status (positive, negative or NA) in tumor cells  
 Total percent positivity of PD-L1 in infiltrating immune cells 
 
The Ventana SP263 assay to measure PD-L1 in tumors is experimental.  As with all tests, there 
is a chance of false positive (the test shows high PD-L1 when it is not there) or false negative 
(the test does not show PD-L1 when it is there) results may occur.   
 
Sample processing and if indicated submission process for PD-L1 testing 
 
Preparing Stored samples for testing 
 Where samples already exist, they should be retrieved from the Bio-Bank storage location.  
These blocks should undergo quality review, prior to evaluation or shipment.  Where it is not 
possible or indicated to ship the block to a testing laboratory, unstained slides should be 
prepared from the paraffin-embedded tumor sample block (described below) prior to 
evaluation or shipment.   
 


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Preparing newly acquired samples for PD-L1 testing 
 If patients are undergoing a biopsy procedure that provides the option to submit newly 
acquired samples, this sample should be used to determine PD-L1 status.  Where clinically 
acceptable, a minimum of 2 core biopsies should be collected and processed to FFPE in a 
single block.  The provision of 2 cores is advised in order to provide sufficient tissue for PD-
L1 assessment.  
 It is recommended that core needle tumor biopsies are collected using an 18 gauge or larger 
needle and the process should be image-guided.  TURBT specimens are preferred.  If this is 
not per the institutions normal practice and a smaller gauge needle is used then the number of 
cores collected should be increased to allow sufficient material for successful PD-L1 testing 
(>100 tumor cells) and embedded in the same block.  If available, a single excisional biopsy 
of at least 4 mm in diameter may substitute for all core biopsies.  
 
Fixation of biopsy samples for PD-L1 testing 
 Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing.  To fix 
newly acquired tissue, place immediately (within 30 min of excision) into an adequate 
volume of 10% v/v neutral buffered formalin (NBF).  Samples should remain in fixative for 
24 – 48 hours at room temperature.   
 It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10 
volume excess) and that large specimens (if any) are incised prior to fixation to promote 
efficient tissue preservation.   
 
Embedding in paraffin for PD-L1 testing 
 An overnight processing schedule into paraffin wax is recommended  
 
Storage of tumor blocks for PD-L1 testing 
 FFPE blocks should be stored at ambient temperature and protected from light until shipment 
by courier at ambient temperature. FFPE blocks are stable under these conditions for an 
indefinite period. 
 
Quality control of samples to be used for PD-L1 testing 
 Tissue should be assessed by the site pathologist prior to PD-L1 testing.   
 Each sample should be reviewed for: 
 Adequate fixation 
 Good preservation of morphology 
 Presence of tumor tissue 
 Histopathology consistent with indication 
 
 Greater than 100 tumor cells are required to determine PD-L1 status – tumor cell content 
must be reviewed prior to testing in order for PD-L1 obtain a valid result.   
 
If indicated, shipping samples to a PD-L1 testing laboratory 
 When submitting sample to for PD-L1 testing the recommendation is to ship the block for 
sectioning to occur at the laboratory. Blocks should be shipped containing enough material to 
to allow a minimum of 5, and preferably 10, sections to be cut (each 4 micron thick) for PD-
L1 testing. 
 


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Sectioning instructions 
 Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, 
unstained slides should be prepared from the paraffin-embedded tumor sample block as 
described below: 
 A minimum of 10 slides x 10 micron (μm) thick and 5 slides x 4 μm thick, unstained 
sections should be provided for PD-L1 testing 
 A new disposable microtome blade must be used for each block to prevent contamination 
between patient samples  
 Slides are stable under these conditions for 6 months. 
 Apply one section per slide to positively-charged Superfrost glass slides  
 The sections should be dried overnight between room temperature and 37°C. Do not dry 
sections at temperatures above 37°C. 
 
Sections should be stored at ambient temperature and protected from light until use or shipment 
to testing lab by courier at ambient temperature. It is recommended that slides are cut freshly 
prior to PD-L1 testing and they are used within 90 days of being cut to obtain PD-L1 status 
8.3 
PD-1 expression on T cells from peripheral blood and IFN-γ in plasma 
Peripheral blood will be collected prior to starting durvaRT, 3-4 weeks post durvaRT and at the 
safety follow up visit-post completion of adjuvant durvalumab. Expression of PD-1 on CD4+ 
and CD8+ T cells will be assessed by flow cytometry. Correlation between the level of PD-1 
expression and clinical outcomes (DCR, PFS, OS) will be analyzed. 
 
Volume of blood: 3 green tops, each with 8cc of blood for each time point per patient- Time 
periods include- baseline, 3-4 weeks post completion of durvaRT and at the safety follow up visit 
post completion of adjuvant durvalumab. 
 
The blood samples need to be shipped on ice (4° C) to Dr. Zheng’s lab within 24 hours for 
processing before saving in liquid nitrogen.  
 
Study Description 
Peripheral blood will be collected at above time periods. Samples will be diluted 1:1 with PBS 
before separation of peripheral blood mononuclear cells (PBMCs) by density gradient 
centrifugation. Cells will be frozen and stored in liquid nitrogen. When assays are performed, 
frozen cells will be thawed and washed in staining buffer. Cells will be then incubated with 
directly conjugated monoclonal antibodies CD3-APC, CD8-APCcy7, CD4-FITC and PD-1-PE 
for 30 minutes at 4°C. Flow cytometry will be performed on a BD Fortessa with subsequent 
analysis using FlowJo Version 8.8.7 software. Analysis will be performed after gating on live 
singlet cells. Percentage of PD-1 positive cells among CD3+CD4+ and CD3+CD8+ T cells 
respectively will be evaluated. Correlation between PD-1 expression clinical outcomes (DCR, 
PFS, OS) will be analyzed. 
 
Plasma cytokines such as IFN-γ: Plasma obtained from peripheral blood collected above for PD-
1 expression will also be used to analyze inflammatory cytokines including but not limited to 
IFN-y. IFN-γ concentration in plasma will be assessed by Bead-based immunoassays. In 
addition, intracellular IFN-γ release by T cells will be assessed by flow cytometry. 


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8.4 
Urine cell free DNA (ucfDNA): 
Urine volume of about 30cc will be collected at baseline and stored for further testing- 
ucfDNA at baseline will be used for further testing.  
We will store the urine at baseline for performing NGS (somatic mutation) on ucfDNA if 
possible.  Please note that this correlative testing will be done only if additional funding is 
available.  
8.5 
Next generation sequencing:  
NGS of tumors pretreatment and post durvaRT and their correlation with response rate for 
durvaRT +adjuvant durvalumab. In addition, we will do next generation sequencing of urine at 
pretreatment and will correlate with tumor sequencing at pretreatment stage. If subjects have 
genetic sequencing analyses performed as per standard of care prior to study and/or at 
progression, those results should be entered into the study database. In that case, NGS testing 
may not be repeated by the study.  
 
We will explore the correlation between somatic mutational statuses- upregulation of specific 
mutation/pathway, mutational burden with clinical outcome. We will also do NGS at baseline on 
ucfDNA and compare it to the tumor NGS for specificity and sensitivity. This will help us 
determine the role of circulating DNA in urine as a non-invasive surrogate marker for tumor 
biopsies.  
 
The samples of available tissue at baseline and post durvaRT will be stored to do NGS for future. 
These will include DNA and RNA sequencing and we will also explore subtyping based on RNA 
expression. NGS will be done upon receipt of funding. The samples will be collected as stated 
above for PD-L1 testing (either a tissue block OR 15 FFPE slides [minimum of 10 slides x 10 
micron (μm) thick and 5 slides x 4 μm thick] plus any leftover surplus tissue after standard of 
care procedure). We will use the leftover specimen after PD-L1 test on tissue for performing 
NGS. Similarly, we will use the available ucfDNA for performing NGS. Please note that this 
correlative testing will be done if additional funding is available. 
 
Pre-treatment whole blood will be collected for germline comparison.  This is also known as a 
somatic baseline sample.   
8.6 
Storage of Biospecimens 
The tissue and urine samples will be shipped from all sites to be stored in the Institute of 
Personalized Medicine’s lab of Penn State Hershey Medical center. Tissues will be collected 
when biopsies are done as part of standard of care so no extra risk is associated with it. Tissue 
and urine will be shipped per standard of care as listed in the lab manual. 
 
The peripheral blood will be shipped to Dr. Hong Zheng’s lab at Penn State Hershey Medical 
Center within 24hours of lab draw. The PBMCs should be shipped on ice (4° C). To avoid 
delays, lab needs to be drawn between Mon-Thursday. Labs should not be drawn on holidays, 
weekends or Fridays. 
 
Some experiments would be performed in Dr. Todd Schell’s lab at Penn State Hershey Medical 
Center. These would include immune biomarkers- Intracellular cytokine release by CD4 and 


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CD8 T cells, and their phenotypic subsets, will be assessed by flow cytometry. Correlation 
between cytokine production and clinical outcomes (RR, PFS, OS) will be analyzed. 
8.7 
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples that were collected for study-
specific correlative research. Hoosier Cancer Research Network (HCRN), 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 and used for future 
unspecified cancer-related research. 
8.8 
Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional samples for future unspecified Big Ten 
Cancer Research Consortium studies. HCRN will manage the banked samples. Samples will be 
banked indefinitely in the HCRN Biorepository.  
 
This includes: 
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to 
treatment on Cycle 1 Day 1 and at Safety Follow Up.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to 
treatment on Cycle 1 Day 1 and at Safety Follow Up. 
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin 
fixed paraffin embedded tumor sample.  
 
Please refer to the CLM for all sample collection, processing, labeling, and shipping instructions. 
8.9 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s study number assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be coded and only 
identified by the subject’s study number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following [42] [43]: 
 
 Response to immunotherapy may be delayed 
 Response to immunotherapy may occur after PD by conventional criteria 
 The appearance of new lesions may not represent PD with immunotherapy 
 SD while on immunotherapy may be durable and represent clinical benefit. 
 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti-
cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anti-
cancer compounds, the study wishes to implement the following in addition to standard RECIST 
1.1 criteria: 
 RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence 


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of clinically significant deterioration.  Treatment with durvalumab will continue between 
the initial assessment of progression and confirmation for progression.  
 
Modification of RECIST as described may discourage the early discontinuation of durvalumab 
and provide a more complete evaluation of its anti-tumor activity than would be seen with 
conventional response criteria.  The efficacy analysis will be conducted by programmatically 
deriving each efficacy endpoint based on modified RECIST 1.1 criteria. 
 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab or with symptomatic 
progression that requires urgent medical intervention (e.g., central nervous system metastasis, 
respiratory failure due to tumor compression, spinal cord compression). 
 
Please note that local PD after concurrent durvaRT can be evaluated by flexible cystoscopy. 
Local PD must be biopsy proven as mentioned in section 7.5.1.  
 
9.1 
Safety and Efficacy variables 
 
 Safety Assessment during phase Ib as primary end point: 
 Safety will be assessed using common terminology criteria for adverse event 
(CTCAE), version 4 at each clinical visit during the course of treatment.  
 
Dose limiting toxicity (DLT) details have been provided in section 5.3.2 and 5.3.3. 
 
DLTs will be counted based on the number of subjects with DLT at a given dose level, not the 
absolute number of DLTs. No single subject can trigger more than one DLT event. 
 
 Efficacy:  
Efficacy will be determined by modified RECIST v1.1. Local response in bladder will also 
be determined by serial cystoscopy. Progression will be determined by modified RECIST 
v1.1 with help of imaging and cystoscopy. Patients will be allowed to continue on the study 
after 1st progression until the PD is confirmed at the next scheduled visit, preferably, and 
no earlier than 4 weeks after the initial assessment of PD in the absence of clinically 
significant deterioration. 
 
Efficacy by cystoscopy:  
At each cystoscopy, tumor staging of disease in the bladder will be decided based upon the intra-
operative findings by urologist, radiology and the pathology report if applicable (flexible 
cystoscopy exam is acceptable if deemed necessary by treating urologist; pathology confirmation 
is needed for confirmation of recurrence in bladder).  
 
Suspected progression by cystoscopy will be defined as any new growth of a three-dimensional 
tumor within the bladder. The appearance of possible carcinoma in situ, defined as flat velvety 
erythematous mucosal patches, will not be deemed disease progression at interval cystoscopy.  
Any suspected tumor progression will trigger a brief cessation of therapy to allow for TURBT 
with repeat maximal resection and pathologic confirmation of viable tumor. Confirmed disease 


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progression, defined as an increase in volume of a three-dimensional, viable, histologically 
confirmed cancer will be recorded as PD.  Progressive disease per cystoscopy must be confirmed 
by pathological diagnosis.  CIS, T1 will not be defined as disease progression. Photographic 
imaging will be performed to provide a record of baseline local disease and at any other 
time cystoscopy is performed if possible. Recording of photographic imaging is strongly 
encouraged by urologist.  
 
If a CR is suspected, confirmatory directed and random biopsies will be performed to rule out 
residual CIS.  In the event that CIS is the only finding, the patient will be deemed a CR and may 
be offered appropriate intravesical mitomycin therapy for CIS.  Intravesical BCG is not allowed 
for this study. Patient will need to come off the study should patient decide to use BCG therapy 
per discussion by urologist. BCG intravesically is permitted after completion of adjuvant 
durvalumab. If T1 recurrence is proven, interruption for TURBT is allowed on the study. 
Intravesical mitomycin is allowed but intravesical BCG is not permitted during the course of 
durvalumab, but can be given after completion of adjuvant durvalumab.  
 
Any cystoscopical findings that suggests persistence of one or more lesion(s) will be classified as 
non-CR/non-PD 
 
The following will be used to define the tumor staging based on NCCN guidelines. 
Tx: Primary tumor cannot be assessed
Ta: Noninvasive papillary carcinoma Tis: Carcinoma in situ
T1: Tumor invades lamina propria 
T2: Tumor invades muscularis propria 
• T2a: Invades superficial muscularis propria (inner half) 
• T2b: Invades deep muscularis propria (outer half) 
T3: Tumor invades perivesical tissue/fat 
• T3a: Invades perivesical tissue/fat microscopically 
• T3b: Invades perivesical tissue fat macroscopically (extravesical mass) 
T4: Tumor invades prostate, uterus, vagina, pelvic wall, or abdominal wall 
• T4a: Invades adjacent organs (uterus, ovaries, prostate stoma) 
• T4b: Invades pelvic wall and/or abdominal wall
 
Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 include the following. 
 
9.2 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 


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9.2.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.3 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
9.4 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
9.5 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
9.6 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1 (Eur J Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete Response 
(CR) 
Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 
mm. 


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Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters
Progressive Disease 
(PD) 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
9.7 
Evaluation of Non-target Lesions 
Complete Response 
(CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 
mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they 
must normalize for a subject to be considered in complete clinical 
response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits
Progressive Disease 
(PD) 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor-investigator with another evaluation by imaging at next 
clinic visit, no sooner than 4 weeks.  
9.8 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
Target Lesions 
Non-Target Lesions** 
New Lesions
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 


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Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. But confirmaory scans need to be done no sooner than 4 
weeks to confirm PD for this study prior to discontinuing treatment.  
**Cystoscopy evaluation will be counted as non-target lesion. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
 
 


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9.9 
Definitions for Response Evaluation – RECIST 1.1 
 
9.9.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.9.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed at next clinic visit no less than four weeks after the 
criteria for response are first met. Stable disease response is defined as disease response that 
meets the criteria for SD for at least duration of 8 weeks. Confirmatory scans for stable disease 
must be performed at next clinic visit, no less than 4 weeks after the criteria for response are first 
met.  
 
9.9.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
 
9.9.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 
9.9.5 Complete Response Rate  
The objective response rate is the proportion of all subjects with confirmed CR according to 
modified RECIST 1.1 and cystoscopy, from the start of treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the start of treatment). 
 
9.9.6 Disease Control Rate: 
The disease control rate is the proportion of all subjects with stable disease (SD) or 8 weeks, or 
partial response (PR), or complete response (CR) according to modified RECIST 1.1 and 
cystoscopy, from the start of treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the start of treatment). 
 
9.9.7 Progression Free Survival Rate at 1year: 
Progression free survival rate at one year is defined as the probability that a patient remains free 
of progression of disease (SD+CR+PR) by modified RECIST 1.1 and cystoscopy at 1 year from 
the start of durvalumab treatment, D1 of durvaRT.  
 
9.9.8 Progression Free Survival 
A measurement from the date of initiation of durvalumab until the criteria for disease 
progression is met as defined by modified RECIST 1.1 and cystoscopy or death occurs. Subjects 
who have not progressed will be right-censored at the date of the last disease evaluation. 
 


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9.9.9 Overall Survival 
Overall survival is defined by the date of initiation of durvalumab to date of death from any 
cause. 
 
10. 
DRUG INFORMATION 
 
10.1 
Durvalumab (MEDI4736) 
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid 
tumors. 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). Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, 
with an overall molecular weight of approximately 149 kDa. Durvalumab 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. 
 
The results from phase I study have led FDA to grant breakthrough therapy designation to 
durvalumab in Feb 2016, for the treatment of patients with PD-L1 positive inoperable or 
metastatic urothelial bladder cancer whose tumor has progressed during or after one standard 
platinum-based regimen. 
 
Encouraging results from this study has led to the design of a phase III study in bladder cancer. 
DANUBE is a phase III study that is evaluating the efficacy of durvalumab alone vs. durvalumab 
plus anti-CTLA4 Mab, tremelimumab vs. standard of care in 1st line setting for metatstatic 
chemo naïve cisplatin eligible and cisplatin ineligible patients. The results are expected by 2018.  
Please refer to section 1.2 for more details.  
 
10.2 
Supplier/How Supplied 
 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab to the site investigator as a 500-mg vial solution for infusion after dilution. 
 
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. 
 
10.3 
Preparation  
See also Section 5.7. See Documents/ Info tab of the EDC for dose calculations on subjects less 
than or equal to 30 kg.   
 
Preparation of infusion bags 


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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. 
 
10.4 
Storage and Stability 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 
275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The 
nominal fill volume is 10 mL. Unopened vials of liquid durvalumab must be stored at 2°C to 8°C 
(36°F to 46°F) and must not be frozen. Store in original carton to protect from light. 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.  
 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 4 hours at room temperature.  The table below summarizes time 
allowances and temperatures. 
 
Durvalumab hold and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 
24 hours at 2°C to 8°C 
Maximum time for IV bag infusion, including interruptions
4 hours at room temperature
 
In the event that either preparation time or infusion time exceeds the time limits outlined above, 
a new dose must be prepared from new vials.  Durvalumab does not contain preservatives, and 
any unused portion must be discarded. 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Receipt and dispensing of trial medication must be recorded by an 
authorized person at the trial site. Clinical supplies may not be used for any purpose other than 
that stated in the protocol.  
 
 
 


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10.5 
Administration 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral vein. 
 
The dose of durvalumab for administration must be prepared by the site’s designated 
Investigational Pharmacy using aseptic technique. 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 or 0.22-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.  
 
10.6 
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.  
 
10.7 
Dispensing 
Durvalumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Durvalumab should be stored in a secure area according to 
local regulations.  It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.8 
Adverse Events 
Adverse events for durvalumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These adverse events are being closely monitored in clinical studies with durvalumab 
monotherapy and combination therapy.  
 
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, type 1 diabetes mellitus, hypophysitis/hypopituitarism, 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: 


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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) 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as: 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires an 
action or intervention by the investigator, or a finding judged by the investigator to represent a 
change beyond the range of normal physiologic fluctuation, should be reported as an AE. 
 
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational 
product) or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product.  
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
subject being enrolled into the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical 


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event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
 
The term AE is used to include both serious and non-serious AEs. 
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
11.1.2 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Definition of Immune-Mediated Adverse Events (imAEs) 
Immune-mediated 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 (BTCRC 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). The AESI 
must be reported via entry into OnCore.    
 
11.1.4 Definition of Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the local investigator to sponsor-investigator via the BTCRC project manager. 
An AESI may be serious or non-serious.  
 


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If the Investigator has any questions in regards to an adverse event (AE) being an imAE, the 
Investigator should promptly contact the sponsor-investigator via the BTCRC project manager. 
 
AESIs observed with 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) 
 Intestinal Perforations 
 
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to: 
 Pericarditis 
 Sarcoidosis 
 Uveitis 
 Other events involving the eye and skin 
 Hematological events 
 Rheumatological events 
 Vasculitis 
 Non-infectious meningitis 
 Non-infectious encephalitis.  
 
It is possible that events with an inflammatory or immune mediated mechanism could occur in 
nearly all organs. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological aetiology are also considered AESIs. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator Brochure. 
 
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.  
 


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Guidelines for the management of subjects with immune-mediated adverse events including 
pneumonitis are outlined in Appendix 2. 
 
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 Appendix 3. 
 
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 
Appendix 2 
 
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN 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. 
 
11.1.4.4 Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab is 
used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  Guidelines on management 
of diarrhea and colitis in patients receiving durvalumab are provided in Appendix 2. 
 


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11.1.4.5 Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Appendix 2. 
 
11.1.4.6 Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Appendix 2. 
 
11.1.4.7 Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Appendix 2. 
 
11.1.4.8 Nephritis 
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to changes in 
renal function (e.g. routine urinalysis, elevated serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc). 
 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, infections etc.). 
 
Steroids should be considered in the absence of clear alternative etiology even for low grade 
events (Grade 2), in order to prevent potential progression to higher grade event.   Guidelines for 
the management of patients with immune-mediated neurotoxic events are provided in Appendix 
2. 
 
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 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, package insert, or when it is not included in the 
informed consent document as a potential risk. Unexpected also refers to AEs that are mentioned 
in the IB as occurring with a class of drugs or are anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation.   


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11.1.6 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 
11.2 
Reporting 
 
11.2.1 Adverse Events 
 AEs will be recorded from time of signed informed consent, throughout the treatment 
period, and until 90 days after discontinuation of study drug(s) or until a new anti-cancer 
treatment starts, whichever occurs first. 
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within OnCore. 
 Adverse events will be assessed by the site investigator for severity, relationship to the 
investigational product, and possible etiologies. 
 All AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 
or baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 Site Requirements for Reporting SAEs to BTCRC Administrative Headquarters 
 SAEs will be reported from time of signed informed consent, throughout the treatment 
period, and until 90 days after discontinuation of study drug(s) or until a new anti-cancer 
treatment starts, whichever occurs first.  
 SAEs will be reported via entry into the OnCore SAE tab within 1 business day of 
discovery of the event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within OnCore.   
 SAEs will be assessed by the site investigator for severity, relationship to the 
investigational product, and possible etiologies. 
 All SAEs, regardless of relation to study drug, will be followed until resolution to ≤ 
Grade 1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 


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The site investigator is responsible for informing the IRB and/or other local regulatory bodies as 
per local requirements. 
 
During the course of the study all SAEs should be proactively followed up for each subject. 
Every effort should be made to obtain a resolution for all events. Once the SAE has resolved, 
sites must submit a follow up via OnCore within a reasonable timeframe.  
 
11.2.2.2 Other events requiring immediate reporting 
 
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 BTCRC AHQ via entry into OnCore within within 1 business day of 
knowledge of the event. BTCRC 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. 
 
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 BTCRC AHQ via entry into OnCore, unless a 
definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) 
that is unrelated to investigational product has been confirmed. BTCRC 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.  
 
Requirements for Reporting Pregnancy 
If a subject becomes pregnant during the course of the study, durvalumab and RT should be 
discontinued immediately. 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 


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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 1 business day of knowledge of the event to BTCRC AHQ at safety@hoosiercancer.org 
on the Pregnancy Report form (See Documents/Info tab of the EDC). BTCRC AHQ will report 
the event to AstraZeneca/MedImmune Patient Safety or designee within 1 business day 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 BTCRC AHQ after outcome is known.  
 
BTCRC AHQ will report the event to AstraZeneca/MedImmune Patient Safety or designee 
within 24 hours using the designated Safety e-mailbox. The designated AstraZeneca 
representative will work with BTCRC AHQ and the Sponsor Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies. 
 
Male subjects should refrain from fathering a child or donating sperm during the study and for 3 
months following the last dose.   
 
Any pregnancy in the partner of a male study subject from the date of the first dose until 90 days 
after the last dose should be reported within 1 business day of knowledge of the event to 
BTCRC AHQ at safety@hoosiercancer.org 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. 
 
11.2.2.3 BTCRC AHQ Requirements for Reporting Events to AstraZeneca 
BTCRC AHQ will report all SAEs, AESIs, and other reportable events to AstraZeneca within 1 
business day of knowledge of the event.  Follow-up information will be provided to 
AstraZeneca 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. 


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11.2.2.4 BTCRC AHQ Responsibilities for Reporting SAEs to FDA 
 
BTCRC AHQ has been designated to manage the Investigational New Drug Application 
associated with this protocol on behalf of the sponsor-investigator. BTCRC AHQ will cross-
reference this submission to AstraZeneca’s parent IND at the time of submission.  
 
BTCRC AHQ will be responsible for all communication with the FDA in accordance with 
21CFR312 including but not limited to the 7 and 15 Day Reports, as well as an Annual Progress 
Report. Additionally, BTCRC AHQ will submit a copy of these reports to AstraZeneca at the 
time of submission to FDA. 
 
BTCRC AHQ will inform the FDA, via a MedWatch/AdEERs form, of any serious or 
unexpected adverse events that occur in accordance with the reporting obligations of 21 CFR 
312.32, and will concurrently forward all such reports to AstraZeneca.  A copy of the 
MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is reported to the 
FDA.  BTCRC AHQ will work with the site and sponsor-investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines. These reports will also be submitted to AstraZeneca at the same time. 
 
Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com. 
 
11.2.3 Sponsor-Investigator Responsibilities 
BTCRC AHQ will send a SAE summary to the sponsor-investigator within 1 business day of 
receipt of SAE data from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
 
11.2.4 IND Safety Reports Unrelated to this Trial 
AstraZeneca will provide BTCRC AHQ with IND safety reports from external studies that 
involve the study drug(s) per their guidelines. BTCRC AHQ will forward the safety reports to 
the sponsor-investigator who will review these reports and determine if revisions are needed to 
the protocol or consent.  BTCRC AHQ will forward these reports to participating sites within 1 
business day of receiving the sponsor-investigator’s review. Based on the sponsor-investigator’s 
review, applicable changes will be made to the protocol and informed consent document (if 
required). All IND safety reports will also be made available to sites via OnCore. 
 
Upon receipt from BTCRC AHQ, site investigators (or designees) are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
 
 
12. 
STATISTICAL METHODS 
 
12.1 
Study Design 
 


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This is a single arm, open-label study phase Ib/II study of durvaRT followed by adjuvant 
durvalumab. Phase Ib will be conducted to determine the safety of durvalumab in combination 
with RT. Phase II will estimate the 1-year PFS and DCR (post completion of durvaRT followed 
by adjuvant durvalumab).   
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
 
Phase Ib :  
To assess the safety of combining durvalumab with RT in that the DLT rate is smaller than 33%. 
Documenting DLTs during the combined durvaRT period. Subjects will be monitored for DLTs 
for 7-weeks.  
 
Phase II:  
1. Estimate the progression free survival (PFS) rate at 1 year. Progression free survival rate at 
one year is defined as the probability that a patient remains free of progression of disease 
(SD+CR+PR) by modified RECIST 1.1 and cystoscopy at 1 year from the start of 
durvalumab treatment, D1 of durvaRT.   
 
2. To estimate the DCR to concurrent durvaRT followed by durvalumab. DCR will be defined 
for this study as rates of patients achieving CR, PR or SD, post completion of concurrent 
durvaRT and adjuvant durvalumab. Response will be determined by modified RECIST 1.1 
 
12.2.2 Definition of Secondary Endpoints 
 
Phase Ib: 
1. Estimate the DCR post completion of concurrent durvaRT. 
2. To correlate the expression of PD-L1 on immunohistochemistry at pre-treatment (TURBT 
specimen if possible) and post- durvaRT treatment (cystoscopy-biopsy 2-3 weeks post 
durvaRT) with DCR.  
 
Phase II: 
1. Estimate the median progression free survival (PFS) time. Median PFS for this cohort will be 
calculated.  
2. Estimate the rate of complete remission (CR) post durvaRT by modified RECIST 1.1 
3. Estimate the overall survival (OS), defined as time from start of treatment, D1, to the date of 
death due to any cause. 
 
12.3 
Sample Size and Accrual 
Statistical Power and Sample Size Considerations: The Phase Ib component consists of one dose 
level only so it requires a maximum of 6 patients. Given the safety is not dose dependent; no 
dose de-escalation will be allowed. For the Phase II component, we hope our therapy will 
increase the rate of PFS at 12 months from 50% to 75%. There is paucity of literature to support 
the exact PFS rate for this subgroup of patients. As this study is expected to enroll higher stage 
patients with T4 or node positive disease, it is assumed that the historic PFS rate is around 50% 


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at 1-year (PFS rate for stage IV patients who achieve CR is around 80% but those who do not 
achieve CR it falls between 0-40%). To reach a statistical power of at least 80% at one-sided 
alpha level of 5% and to allow for 10% drop out rate, a total of 26 patients are needed for this 
part which allows for 10% dropout. The second primary objective of Phase II is to estimate the 
disease control rate (DCR), which we assume to be about 75%. With 26 combined patients in 
Phase Ib and Phase 2, we can, with 90% confidence, estimate DCR within 14% error. 
 
6 patients from the in Phase Ib will be included in the analysis with patients from the Phase II 
portion for a total number of patients of 26. 
 
12.4 
Analysis Datasets 
 
Patients to be included for analyses in phase Ib: 
1. All patients who complete the entire course of durvaRT. 
2. All patients who get at least one dose of durvalumab who experience DLTs. However if a 
patient permanently discontinued the trial due to non-toxicity reasons related to RT or 
durvalumab, then that patient will not be included in the phase 1 analyses.  
 
Patients to be included in the phase II analyses: 
 
PFS analyses: We will follow the intent-to-treat principle and therefore will include all patients 
who are enrolled and completed at least one dose of the treatment. We will also include roll over 
patients from phase Ib. For PFS, the survival analysis can handle censoring data for those who 
drop out early for reasons unrelated to disease or toxicity. For those who may drop out for 
reasons pertaining to disease or toxicity, they will be followed up for an accurate time of disease 
progression/survival unless patient withdraws consent.  
 
DCR analyses: For DCR, the co-primary end point for phase II part, we will include all patients 
who complete the entire course of durvaRT followed by adjuvant durvalumab (regardless of 
duration of adjuvant period of treatment) and whose disease response could be determined. 
Patients who discontinue the trial due to non-disease related or non-toxicity reasons whose 
disease response cannot be determined during the course of therapy will be excluded from the 
DCR analyses. We will also include roll over patients from the phase Ib part provided they 
complete the entire course of treatment per protocol.  
 
12.5 
Assessment of Safety 
Any subject who receives at least one dose of treatment on this protocol should be evaluable for 
toxicity. We will use the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4, to record toxicity.  Please refer back to the Study Calendar 
for the schedule of toxicity assessment. 
 
12.6 
Assessment of Efficacy 
All subjects with measurable disease who have received at least one cycle of treatment and have 
their disease re-evaluated will be evaluable for assessment of progression free survival and 
objective response.  Please refer to section 9.  
 


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12.7 
Data Analysis Plans 
 
12.7.1 Analysis Plans for Primary Objective 
Descriptive statistics will be used in the study to analyze patient’s characteristics and 
demographics. In particular, patient age, race, weight, ECOG performance status will be 
described. For phase Ib, the incidence and type of DLTs will be tabulated and reported at the 
dose level. Other toxicity information will be summarized via frequency tables by type and grade 
of toxicity. DLTs will be recorded during the entire course of durvaRT. The combined treatment 
will be considered safe to continue to phase II part of the study if 0 or 1 patient (out of 6) 
experiences DLT. 
 
For phase II, the primary endpoints are the progression free survival (PFS) status at 1 year, and 
the disease control status (CR+PR+SD) post completion of concurrent durvaRT followed by 
adjuvant durvalumab. The PFS will be analyzed using the Kaplan–Meier estimator with 
particular emphasis for one-year survival rate. The disease control status will be summarized 
using point estimate values of the relative frequency and their 95% confidence intervals. 
Appropriate statistical tests will be used to compare the PFS rate and the disease control rate 
from the study sample to the existing values from historical cohorts. 
 
12.7.2 Analysis Plans for Secondary Objectives 
The secondary endpoints include the progression-free survival (PFS) time, overall survival (OS) 
time, and the rate of complete remission (CR) post durvaRT by RECIST/cystoscopy. The 
survival (PFS and OS) time will be graphical displayed by the Kaplan-Meier survival curve. The 
median survival time and its 95% CI will be reported. The statistical methods use for analyzing 
the CR rate and relapse rate will be similar to that for the disease control rate. The bi-variate 
relationship between the outcome variables and some key some key clinical and demographic 
variables, such as tumor stage, ECOG status, smoking status, and gender, etc. will be examined 
by Fisher’s exact test or Kaplan-Meier test when appropriate. For the factors that show 
marginally significant relationship (for example, p<0.1), their relationship with the outcome 
variable will be reexamined by using some multiple regression methods, such as multiple logistic 
regression or multiple Cox proportional hazard regression. All analyses will be performed using 
statistical software SAS version 9.4 or higher (SAS Institute, Cary, NC, USA). The statistical 
significance level to be used is 0.05. 
 
12.7.3 Analysis Plans for Exploratory Objectives 
For the exploratory objectives, the relationship between PD-L1 expression on tumor and tumor 
infiltrating cells when compared to clinical outcome (DCR, PFS, OS): IHC will be performed as 
previously reported [41], and all IHC will be assessed by clinical pathologists through the use of 
the Allred system, which consists of the summation of IHC intensity and distribution of 
immunoreactivity.  Correlations amongst IHC scores for PD1, PDL1 and FOXP3, and between 
the extent of positive staining and tumor stage will be assessed using Spearman rank coefficients.  
The extended Mantel-Haenszel test will be used to assess correlations between IHC scores after 
adjusting for tumor stage.  The association between IHC score and response to durvalumab 
(DCR, PFS, OS) will be tested via the application of Mann-Whitney U test following 
dichotomization at the mean. For progression-free survival (recurrence) analysis, univariate 
analyses will be performed using log rank tests and visualized using Kaplan-Meier survival 


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curves.  Variables associated with adverse prognosis based on previous studies and variables 
with a P <0.10 on univariate analysis will also be included in a multivariate analysis using a Cox 
proportional hazards model if needed. 
 
For other exploratory objectives in phase II study: PD-1 expression on T-cells in PBMC will be 
correlated with clinical outcome using two-sample T-test or nonparametric Wilcoxon Rank-Sum 
test. The correlation of selected genes obtained by next generation sequencing (NGS) will be 
correlated to clinical outcomes using similar statistical methods. The overall false discovery rate 
(FDR) will be controlled at 0.05 level.  
 
12.7.4 Subgroup Analyses 
Planned subgroup analysis will be done to compare differences in clinical outcome (DCR and 
PFS rate, mPFS, OS) with tumor stage (T2, T3, T4), lymph node positivity, ECOG PS (0/1 vs. 
2), histology (pure urothelial vs. mixed with predominant urotheial component), chemotherapy 
exposure prior to starting durvaRT (chemonaïve subjects vs. post chemotherapy patients), 
maximal TURBT (yes vs. no).   
 
12.7.5 Other Planned Analyses 
Descriptive statistics will be used in the study to analyze patient’s characteristics and 
demographics. In particular, patient age, race, weight, ECOG performance status will be 
described. 
 
12.8 
Interim Analysis/Criteria for Stopping Study 
Interim analysis will be performed at the discretion of the Data Safety Monitoring Committee to 
monitor study progress. Interim reports with statistical analyses are prepared every six months 
until the initial manuscript reporting the treatment results has been submitted. The reports 
contain: 
a) Patient accrual rate with a projected accrual completion date, 
b) Pretreatment characteristics of accrued patients, and  
c) Frequency and severity of toxicities. 
 
The interim reports will not contain the results from the treatment comparisons with respect to 
the efficacy endpoints (1-year progression-free survival rate, disease control rate, etc.). The Data 
and Safety Monitoring Committee will review the accrual to the study and the rate of adverse 
events on the study at least twice per year until the initial results of the study have been presented 
to the scientific community. 
 
13. 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the Penn State Cancer Institute’s DSMP. 
 
BTCRC AHQ oversight activities include: 
 Review all adverse events requiring expedited reporting as defined in the protocol 
 Notify participating sites of adverse events requiring expedited reporting 


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 Provide trial accrual progress, safety information, and data summary reports to the 
sponsor-investigator 
 Submit data summary reports to the lead institution Data Safety Monitoring Board for 
review as per their DSMP 
 
13.2 
Penn State Cancer Institute Data Safety Monitoring Board 
The study will undergo review by the Penn State Cancer Institute Data Safety Monitoring Board. 
 
BTCRC AHQ will provide the Penn State Cancer Institute DSMB with the following: 
 Adverse event summary report 
 Audit results, if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The Penn State Cancer Institute DSMB will review study data semi-annually.  Documentation of 
DSMC reviews will be provided to sponsor-investigator and BTCRC AHQ.  Issues of immediate 
concern by the DSMB will be brought to the attention of the sponsor-investigator and other 
regulatory bodies as appropriate.  The sponsor-investigator will work with BTCRC AHQ to 
address the DSMB’s concerns.  
  
13.3 
Data Quality Oversight Activities 
Remote validation of Oncore data will be completed on a continual basis throughout the life 
cycle of 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. 
 
Monitoring visits to the trial sites will be made periodically during the trial to ensure key aspects 
of the protocol are followed. Additional for-cause visits may occur as necessary. Source 
documents will be reviewed for verification of agreement with data entered into OnCore.  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 BTCRC AHQ or its designee. 
 
The trial site may also be subject to quality assurance audit by AstraZeneca/ MedImmune or its 
designee as well as inspection by appropriate regulatory agencies. 
 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. The 
sponsor-investigator has delegated responsibility to BTCRC AHQ for registering the trial and 
posting the results on clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a 


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central contact number for further information on appropriate trial locations and study site 
contact information. 
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
BTCRC AHQ will serve as the Clinical Research Organization for this trial. Data will be 
collected through the web-based clinical research platform, OnCore, a system compliant with 
Good Clinical Practices and Federal Rules and Regulations. BTCRC AHQ personnel will 
coordinate and manage data for quality control assurance and integrity. All data will be collected 
and entered into OnCore by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in OnCore and correlative results will be 
captured in OnCore 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 OnCore, according to study-specific 
objectives. Please see the Data and Safety Oversight Process (DSOP) guidelines for further 
details.  
 
The completed dataset is housed at BTCRC 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 BTCRC AHQ. After the initial publication, the 
complete data set will be available to all BTCRC institutions. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/BTCRC AHQ, the site investigator 
agrees to keep records, including the identity of all subjects (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition.  All source documents are to remain in the 
subject’s file and retained by the site investigator in compliance with local and federal 
regulations. No records will be destroyed until BTCRC AHQ confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, BTCRC AHQ, AstraZeneca/ MedImmune, IRB, or government 
agencies, like the FDA, may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws. 


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If the results of the study are published, the subjects’s identity will remain confidential. 
 
15. 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB.  The site investigator must submit written approval by the IRB to BTCRC 
AHQ before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit subjects for the study.  The protocol must be re-approved by the IRB as local regulations 
require.  
 
Progress reports and notifications of adverse events will be provided to the IRB according to 
local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki. Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study.  Subjects must 
also be notified they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study.  The site investigator must store the original, signed 
informed consent form.  A copy of the signed informed consent form must be given to the 
subject. 
 


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APPENDIX 1 
Appendix 2. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and 
Non Immune-mediated Reactions for Durvalumab Monotherapy (17 October 2019 Version) 
General Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4 (unless indicated otherwise). 
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 of the start of the immune-mediated adverse 
event (imAE) 
 
Grade 3 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, 
infections, etc.) to a possible immune-mediated event 
- In the absence of a clear alternative etiology, all 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 PO 1-2mg/kg/day 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 specialistsubspecialty consultation. 
- If symptoms recur or worsen during corticosteroid 
tapering (28 days of taper), increase the corticosteroid 
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 treatment 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 site Investigator or 
treating physician’s clinical judgement, and  
3) doses of prednisone are at less than or equal to 10mg/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: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 


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Appendix 2. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and 
Non Immune-mediated Reactions for Durvalumab Monotherapy (17 October 2019 Version) 
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). 
dose (prednisone dose [e.g. up to 2-4mg/kg/day PO or 
IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a 
slower rate (> 28 days of taper) 
- More potent immunosuppressives such as TNF 
inhibitors (e.g. infliximab; also refer to the individual 
sections of the immune mediated 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.
  
 


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APPENDIX 3 
Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI 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  
1-2mg/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 2-4mg/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 
(e.g. infliximab at 5mg/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 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
days and consider prophylactic antibiotics, antifungal 
or anti PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections) 
- Consider pulmonary and infectious disease consult 
- Consider, as necessary, discussing with study 
sponsor-investigator.
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 (e.g. 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)
Diarrhea/ Colitis 
Large intestine 
perforation/ 
Intestine 
perforation 
Any Grade 
General Guidance 
For Any Grade: 
- Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency 
over baseline or blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal signs, and 
ileus). 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
- When symptoms or evaluation indicate a perforation 
is suspected, consult a surgeon experienced in 
abdominal surgery immediately without any delay. 
- Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections), including testing for 
clostridium difficile toxin, etc. 
- Steroids should be considered in the absence of clear 
alternative etiology, even for low grade events, in 
order to prevent potential progression to higher grade 
event, including perforation. 
- Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis.
Grade 1 
(Diarreha: stool 
frequency of <4 per 
day over baseline)  
(Colitis: 
asymptomatic; 
clinical or 
diagnostic 
observations only) 
No dose modification 
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) 
(Perforation: 
symptomatic; 
medical 
intervention 
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 1-2 mg/kg/day PO or IV 
equivalent, GI consult should be obtained for 
consideration of further workup such as imaging 
and/or colonoscopy, to confirm colitis and rule out 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
indicated*) 
 
 
 
 
 
 
 
 
 
 
* “medical 
intervention” is not 
invasive 
perforation, and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started.  
- If still no improvement within 3-5 days despite 2-
4mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5mg/kg 
once every 2 weeks. Caution: Important to rule out 
bowel perforation and refer to infliximab label for 
general guidance before using infliximab.   
- Consider, as necessary, discussing with sponsor-
investigator 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).
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, medi-
cal intervention 
indi-cated, 
peritoneal signs; 
Grade 4 colitis: 
life-threatening 
Grade 3 
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade 
≤1 within 14 days; study 
drug/study regimen can be 
resumed after completion of 
steroid taper. 
 
Grade 4 
Permanently discontinue study 
drug/ study regimen. 
For Grade 3 or 4: 
- Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent  
- Monitor stool frequency and volume and maintain 
hydration   
- Urgent GI consult and imaging and/or colonoscopy 
as appropriate. 
- If still no improvement within 3-5 days of IV 
methylprednisolone 2 to 4mg/kg/day or equivalent, 
promptly start further immunosuppressives (e.g. 
infliximab at 5mg/kg once every 2 weeks).  Caution: 
Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before 
using infliximab. If perforation is suspected, consult a 
surgeon experienced in abdominal surgery 
immediately without any delay. 
- Once improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, 
antifungals and anti PJP treatment (please refer to 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
consequences, 
urgent intervention 
indicated) 
(Grade 3 
Perforation: severe 
symptoms, 
elective* operative 
intervention 
indicated; Grade 4 
Perforation: life-
threatening 
consequences, 
urgent intervention 
indicated) 
*This guidance 
anticipates that 
Grade 3 operative 
interventions of 
perforations are 
usually not elective
current NCCN guidelines for treatment of cancer-
related infections). 
Hepatitis 
(Elevated 
LFTs) 
Infliximab 
should not be 
used for 
management of 
Immune Related 
Hepatitis 
Any Elevations in 
AST, ALT or 
Total Bili (TB) as 
Described Below 
General Guidance  
For Any Elevations Described: 
- Monitor and evaluate liver function test: AST, ALT, 
ALP and total bilirubin  
- Evaluate for alternative etiologies (e.g., viral 
hepatitis, disease progression, concomitant 
medications). 
AST or ALT 
>ULN and 
≤3.0×ULN if 
baseline normal, 
1.5-3.0×baseline if 
baseline 
abnormal; and/or 
TB > ULN and 
No dose modification 
 
If it worsens, treat as described 
for elevations in the row below 
 
- Continue LFT monitoring per protocol   


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
 
≤1.5×ULN if 
baseline normal, 
>1.0-1.5×baseline 
if baseline 
abnormal 
AST or ALT 
>3.0×ULN and 
≤5.0×ULN if 
baseline normal, 
>3-5×baseline if 
baseline 
abnormal; and/or 
TB >1.5×ULN and 
≤3.0×ULN if 
baseline normal, 
>1.5- 3.0×baseline 
if baseline 
abnormal 
Hold Study drug/study regimen 
dose until resolution to AST or 
ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, or 
to AST or ALT ≤3.0×baseline 
and/or TB ≤1.5×baseline if 
baseline abnormal. 
 If toxicity worsens then treat as 
Grade 3 or Grade 4. 
 If improves to ≤ Grade 1 or 
baseline, resume study 
drug/study regimen after 
completion of steroid taper. 
- Regular and frequent checking of LFTs (e.g. every 1-
2 days) until elevations of these are improving or 
resolved.   
- If no resolution to AST or ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB ≤1.5×baseline if baseline 
abnormal, in 1 to 2 days, consider, as necessary, 
discussing with with sponsor-investigator. 
- If event is persistent (> 3-5 days) or worsens, 
promptly start prednisone 1-2mg/kg/day PO or IV 
equivalent.  
- If still no improvement within 3-5 days despite 1-
2mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup and prompt treatment 
with IV methylprednisolone 2-4mg/kg/day. 
- If still no improvement within 3-5 days despite 2-
4mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil)a. 
Discuss with sponsor-investigator if mycophenolate 
mofetil is not available.  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)a.
AST or ALT 
>5.0×ULN if 
baseline normal, 
For elevations in transaminases ≤ 
8 × ULN, and/or in TB ≤5×ULN if 
baseline normal, or for elevations 
- 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 
PLEASE SEE 
shaded area 
immediately 
below this section 
to find guidance 
for management 
of “Hepatitis 
(elevated LFTS)” 
in HCC patients 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
>5×baseline if 
baseline 
abnormal; and/or 
TB >3.0×ULN if 
baseline normal; 
>3.0×baseline if 
baseline abnormal 
in transaminases ≤8×baseline 
and/or TB ≤5×baseline if baseline 
abnormal:  
 Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤3.0×ULN and/or TB 
≤1.5×ULN  if baseline normal, 
or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline 
abnormal 
 Resume study drug/study 
regimen if elevations 
downgrade AST or ALT 
≤3.0×ULN and/or TB 
≤1.5×ULN  if baseline normal, 
or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline 
abnormal within 14 days and 
after completion of steroid 
taper. 
 Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade as 
described in bullet above within 
14 days.  
For elevations in transaminases > 
8 × ULN or elevations in bilirubin 
> 5 × ULN if baseline normal, or 
for elevations in transaminases 
>8×baseline and/or TB 
>5×baseline if baseline abnormal, 
permanently discontinue study 
mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with immunosuppressive 
therapy (mycophenolate mofetil).  Discuss with 
sponsor-investigator 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)a. 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
drug/study regimen.  
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (ALT 
and /or AST > 3x ULN + bilirubin 
> 2x ULN without initial findings 
of cholestasis (i.e. elevated alk 
phos) and in the absence of any 
alternative cause.b
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 
Any Elevations in 
AST, ALT or TB 
as Described 
Below 
General Guidance 
For Any Elevations Described: 
- Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB. 
- Evaluate for alternative etiologies (e.g., viral 
hepatitis, disease progression, concomitant 
medications, worsening of liver cirrhosis [e.g., portal 
vein thrombosis]). 
- For HBV+ patients: evaluate quantitative HBV viral 
load, quantitative HBsAg, or HBeAg 
- For HCV+ patients: evaluate quantitative HCV viral 
load 
- Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral medications for any patient with an elevated 
HBV viral load >2000 IU/ml 
- Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral HCV medications if HCV viral load 
increased by ≥2-fold 
- For HCV+ with HBcAB+: Evaluate for both HBV 
and HCV as above 
THIS shaded 
area is guidance 
only for 
management of 
“Hepatitis 
(elevated LFTs)” 
in HCC patients  


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
bilirubin or signs 
of DILI/liver 
decompensation 
 
Isolated AST or 
ALT >ULN and 
≤5.0×ULN, 
whether normal or 
elevated at baseline 
 No dose modifications. 
 If ALT/AST elevations 
represents significant 
worsening based on 
investigator assessment, then 
treat as described for elevations 
in the row below. 
For all transaminase elevations, 
see instructions at bottom of 
shaded area if transaminase rise is 
not isolated but (at any time) 
occurs in setting of either 
increasing bilirubin or signs of 
DILI/liver decompensation 
 
 
Isolated AST or 
ALT >5.0×ULN 
and ≤8.0×ULN, if 
normal at baseline 
 
Isolated AST or 
ALT >2.0×baseline 
and ≤12.5×ULN, if 
elevated >ULN at 
baseline 
 
Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤5.0×ULN. 
 
If toxicity worsens, then treat 
as described for elevations in 
the rows below. 
 
If toxicity improves to to AST 
or ALT ≤5.0×ULN, resume 
study drug/study regimen after 
completion of steroid taper. 
- Regular and frequent checking of LFTs (e.g., every 1 
to 3 days) until elevations of these are improving or 
resolved. 
- Recommend consult hepatologist; consider 
abdominal ultrasound, including Doppler assessment 
of liver perfusion. 
- Consider, as necessary, discussing with study 
physician. 
- If event is persistent (>3 to 5 days) or worsens, and 
investigator suspects toxicity to be immune-mediated 
AE, recommend to start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
- If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup and treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
- If still no improvement within 3 to 5 days despite 2 to 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
4 mg/kg/day of IV methylprednisolone, consider 
additional abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and consider 
starting immunosuppressives (i.e., mycophenolate 
mofetil).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab 
should NOT be used. 
 
Isolated AST or 
ALT >8.0×ULN 
and ≤20.0×ULN, if 
normal at baseline 
 
Isolated AST or 
ALT >12.5×ULN 
and ≤20.0×ULN, if  
elevated >ULN at 
baseline 
 
Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤5.0×ULN 
 
Resume study drug/study 
regimen if elevations 
downgrade to AST or ALT 
≤5.0×ULN within 14 days and 
after completion of steroid 
taper. 
 
Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to 
AST or ALT ≤5.0×ULN within 
14 days 
 
Permanently discontinue study 
drug/study regimen for any 
case meeting Hy’s law criteria, 
in the absence of any 
alternative cause.b 
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).a 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
 
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 each level of transaminase rise as instructed for the next highest level of transaminase rise. For example, 
manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or 
ALT >2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST 
or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if  elevated >ULN at 
baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine)  
Any Grade  
General Guidance 
 
For Any Grade: 
- Consult with nephrologist 
- Monitor for signs and symptoms that may be related 
to changes in renal function (e.g. routine urinalysis, 
elevated serum BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decrease 
in urine output, or proteinuria).  
- Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression or 
infections). 
- Steroids should be considered in the absence of clear 
alternative etiology even for low grade events (Grade 
2), in order to prevent potential progression to higher 
grade event.
Grade 1  
[Serum Creatinine 
> 1-1.5 × baseline;  
> ULN to 1.5 × 
ULN]  
No dose modification 
For Grade 1:  
- Monitor serum creatinine weekly and any 
accompanying symptom 
 If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
 If creatinine worsens, depending on the severity, 
treat as Grade 2, 3 or 4.  
- Consider symptomatic treatment including hydration, 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
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 
drug/study regimen after 
completion of steroid taper. 
For Grade 2:  
- Consider symptomatic treatment including hydration, 
electrolyte replacement, and diuretics.  
- Carefully monitor serum creatinine every 2-3 days 
and as clinically warranted. 
- Consult nephrologist and consider renal biopsy if 
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 1-2 mg/kg/day PO or IV 
equivalent, additional workup should be considered 
and prompt treatment with IV methylprednisolone at 
2-4mg/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).a 
- When event returns to baseline, resume study 
drug/study regimen and routine serum creatinine 
monitoring per study protocol.
Grade 3 or 4  
(Grade 3:  Serum 
Creatinine > 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 1-2 mg/kg/day PO or IV 
equivalent, additional workup should be considered 
and prompt treatment with IV methylprednisolone 2-


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
4mg/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).a
Rash or 
Dermatitis 
(including 
Pemphigoid) 
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 
SPONSOR-INVESTIGATOR SHOULD BE 
CONTACTED AND STUDY DRUG 
DISCONTINUED IF SUSPECT STEVENS-
JOHNSON SYNDROME OR TOXIC 
EPIDERMAL NECROLYSIS.
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 study 
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 and promptly start systemic 
steroids prednisone 1-2 mg/kg/day PO or IV 
equivalent.   
- Consider skin biopsy if persistent for >1-2 weeks or 
recurs 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI 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)a 
- Consider, as necessary, discussing with sponsor-
investigator. 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
thyroiditis, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
and adrenal 
insufficiency; 
exocrine event 
of amylase/ 
lipase increased 
also included in 
this section) 
Any Grade  
(Depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 4 
for defining the 
CTC grade 
/severity)  
General Guidance 
For Any Grade: 
- Consider consulting an endocrinologist for endocrine 
events. 
- Consider, as necessary, discussing with sponsor-
investigator. 
- 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, 
polypipsia, polyuria, hypotension and weakness. 
- Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression 
including brain metastases or infections). 
- Depending on the suspected endocrinopathy, monitor 
and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine and related labs 
(e.g., blood glucose and ketone levels, HgA1c).  
- If a patient experiences an AE that is thought to be 
possibly of autoimmune nature (e.g., thyroiditis, 


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Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
pancreatitis, hypophysitis, diabetes insipidus), the 
investigator should send a blood sample for 
appropriate autoimmune antibody testing.
Grade 1 
No dose modification 
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 endocrinologist 
consult. 
Grade 2  
For Grade 2 endocrinopathy other 
than amylase/lipase elevation, 
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 at the next scheduled 
dose once event stabilizes and 
after completion of steroid taper. 
Patients with endocrinopathies 
who may require prolonged or 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
- Consult endocrinologist to guide evaluation of 
endocrine function, and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. 
- For all patients with abnormal endocrine work up, 
except those with amylase/lipase elevation, isolated 
hypothyroidism or Type 1 DM, and as guided by 
endocrinologist, consider short-term, corticosteroids 
(e.g., 1-2mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g. hydrocortisone, 
sex hormones). 


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Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
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, and  
3) doses of prednisone are ≤ 
10mg/day or equivalent. 
- Patients with asymptomatic amylase/lipase elevation 
may continue study drug/ regimen without 
interruption. For patients with symptomatic 
amylase/lipase elevation hold study drug/ regimen 
until subject is clinically stable, asymptomatic, and 
amylase/lipase is ≤ grade 2. Consider steroids and 
further tests at physician discretion per standard of 
care to rule out any alternative etiology (e.g., 
pancreatitis). 
- Isolated hypothyroidism may be treated with 
replacement therapy without treatment interruption 
and without corticosteroids. 
- Isolated Type 1 diabetes mellitus (DM) may be 
treated with appropriate diabetic therapy, without 
study drug/study regimen interruption, and without 
corticosteroids. 
- Once patients on steroids are improving, gradually 
taper immunosuppressive steroids (as appropriate and 
with guidance of endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections)a. 
- For patients with normal endocrine work up (lab 
assessment or MRI scans), repeat labs/MRI as 
clinically indicated.
Grade 3 or 4 
 For Grade 3 or 4 
endocrinopathy other than 
amylase/lipase elevation, 
hypothyroidism and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled. 
 Study drug/study regimen can 
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 amylase/lipase elevation, isolated 
hypothyroidism or Type 1 DM, and as guided by an 
endocrinologist, promptly initiate empiric IV 


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Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
be resumed once event 
stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(e.g., adrenal insufficiency) can be 
retreated with study drug/study 
regimen on the following 
conditions: 
1) The event stabilizes and is 
controlled. 
2) The patient is clinically stable 
as per investigator or treating 
physician’s clinical 
judgement. 
3) Doses of prednisone are 
≤10 mg/day or equivalent. 
methylprednisolone 1 to 2 mg/kg/day or equivalent as 
well as relevant hormone replacement (e.g., 
hydrocortisone, sex hormones). 
- For adrenal crisis, severe dehydration, hypotension, 
or shock: immediately initiate intravenous 
corticosteroids with mineralocorticoid activity. 
- Patients with asymptomatic amylase/lipase elevation: 
hold study drug/ regimen until subject is clinically 
stable and amylase/lipase is ≤ grade 2. For patients 
with symptomatic amylase/lipase elevation hold 
study drug/ regimen until subject is clinically stable, 
asymptomatic, and amylase/lipase is ≤ grade 2. 
Consider steroids and further tests at physician 
discretion per standard of care to rule out any 
alternative etiology (e.g., pancreatitis) 
- Isolated hypothyroidism may be treated with 
replacement therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
- Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study 
drug/study regimen interruption, and without 
corticosteroids. 
- Once patients on steroids are improving, gradually 
taper immunosuppressive steroids (as appropriate and 
with guidance of endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections).a 
Neurotoxicity 
(to include but 
not limited to 
limbic 
encephalitis, 
autonomic 
Any Grade  
(depending on the 
type of 
neurotoxicity, refer 
to NCI CTCAE v4 
for defining the 
General Guidance 
For Any Grade: 
- Patients should be evaluated to rule out any 
alternative etiology (e.g., disease progression, 
infections, metabolic syndromes or medications).  
- Monitor patient for general symptoms (headache, 
nausea, vertigo, behavior change, or weakness).


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Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre) 
CTC grade/ 
severity) 
- Consider appropriate diagnostic testing (e.g. 
electromyogram and nerve conduction 
investigations). 
- Symptomatic treatment with neurological consult as 
appropriate.
Grade 1 
Permanently discontinue study 
drug/study regimen
For Grade 1: 
See “Any Grade” recommendations above.
Grade 2 
Permanently discontinue study 
drug/study regimen 
For Grade 2:  
- Consider, as necessary, discussing with the sponsor-
investigator 
- Obtain neurology consult  
- Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin or duloxetine). 
- Promptly start systemic steroids prednisone 1-
2mg/kg/day PO or IV equivalent . 
- If no improvement within 3-5 days despite 1-
2mg/kg/day prednisone PO or IV equivalent, 
consider additional workup and promptly treat with 
additional immunosuppressive therapy (e.g. IV IG).
 
Grade 3 
Permanently discontinue study 
drug/study regimen
For Grade 3 or 4: 
- Consider, as necessary, discussing with sponsor-
investigator. 
- 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.
Grade 4 
Permanently discontinue study 
drug/study regimen 
Peripheral 
neuromotor 
Any Grade 
General Guidance 
For Any Grade: 
- The prompt diagnosis of immune-mediated 


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Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
syndromes 
(such as 
Guillain-Barre 
and Myasthenia 
Gravis) 
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 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.  
- Important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment 
should be started with IV IG and followed by 
plasmapheresis if not responsive to IV IG.
Grade 1 
No dose modification 
For Grade 1: 
- Consider, as necessary, discussing with the sponsor-
investigator


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
- 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. 
For Grade 2:  
- Consider, as necessary, discussing with the sponsor-
investigator 
- 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 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 
IV IG. Such decisions are best made in 
consultation with a neurologist, taking into 
account the unique needs of each patient. 
o If myasthenia gravis-like neurotoxicity 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 Important to consider here that the use of steroids 


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Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
as the primary treatment of Guillain-Barre is not 
typically considered effective.  
o Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG.
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen 
dose until resolution to ≤ Grade 1. 
Permanently discontinue study 
drug/study regimen if Grade 3 
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 sponsor-
investigator 
- Recommend hospitalization 
- Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS 
o Steroids may be successfully used to treat 
myasthenia gravis.  They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IV IG. 
o If myasthenia gravis-like neurotoxicity present, 
consider starting acetylcholine esterase (AChE) 
inhibitor therapy in addition to steroids. Such 
therapy, if successful, can also serve to reinforce 
the diagnosis. 
GUILLAIN-BARRE:  
o Important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective.  
o Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG.
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis. 
For Any Grade: 
- The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in patients with 
baseline cardiopulmonary disease and reduced 


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Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
cardiac function.  
- Consider, as necessary, discussing with the study 
physician. 
- Monitor patients for signs and symptoms of 
myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral edema). 
As some symptoms can overlap with lung toxicities, 
simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant 
pericardial effusion). A Cardiology consultation 
should be obtained early, with prompt assessment of 
whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
- Initial work-up should include clinical evaluation, 
BNP, cardiac enzymes, ECG, echocardiogram 
(ECHO), monitoring of oxygenation via pulse 
oximetry (resting and exertion), and additional 
laboratory work-up as indicated. Spiral CT or cardiac 
MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
- Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections)
 
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 
 If Grade 2 -- Hold study 
drug/study regimen dose until 
For Grade 2-4: 
- Monitor symptoms daily, hospitalize.


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Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
Grade 2: 
Symptoms with 
mild to moderate 
activity or exertion 
 
Grade 3: Severe 
with symptoms at 
rest or with 
minimal activity or 
exertion; 
intervention 
indicated 
 
Grade 4: Life-
threatening 
consequences; 
urgent intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support) 
resolution to Grade 0. If 
toxicity rapidly improves to 
Grade 0, then the decision to 
reinitiate study drug/study 
regimen will be based upon 
treating physician’s clinical 
judgment and after completion 
of steroid taper. If toxicity does 
not rapidly improve, 
permanently. discontinue study 
drug/study regimen. 
 If Grade 3-4, permanently 
discontinue study drug/study 
regimen. 
- Promptly start IV methylprednisolone 2 to 
4 mg/kg/day or equivalent after Cardiology 
consultation has determined whether and when to 
complete diagnostic procedures including a cardiac 
biopsy. 
- Supportive care (e.g., oxygen). 
- If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). 
Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab. 
- Once the patient is improving, gradually taper 
steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals, or anti-PJP treatment (refer to 
current NCCN guidelines for treatment of cancer-
related infections).a 
Myositis/ 
Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
- Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain 
occurs in proximal muscles including upper arms, 
thighs, shoulders, hips, neck and back, but rarely 
affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing 
can occur and progress rapidly. Increased general 
feelings of tiredness and fatigue may occur, and there 
can be new-onset falling, difficulty getting up from a 
fall, and trouble climbing stairs, standing up from a 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
seated position, and/or reaching up. 
- If poly/myositis is suspected, a Neurology 
consultation should be obtained early, with prompt 
guidance on diagnostic procedures. Myocarditis may 
co-occur with poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, refer to 
guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously 
unknown) autoimmune disorder, consider 
Rheumatology consultation. 
- Consider, as necessary, discussing with the study 
physician. 
- Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory 
work-up as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider whether 
a rheumatologist consultation is indicated and could 
guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as 
anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of 
the muscles, and/or a muscle biopsy. Consider 
Barium swallow for evaluation of dysphagia or 
dysphonia. 
- Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
- Monitor and closely follow up in 2 to 4 days for 
clinical symptoms and initiate evaluation as clinically 
indicated. 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
- Consider Neurology consult. 
- Consider, as necessary, discussing with the study 
physician. 
 
Grade 2 
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental 
activities of daily 
living [ADLs]) 
Hold study drug/study regimen 
dose until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days 
or if there are signs of respiratory 
insufficiency. 
For Grade 2: 
- Monitor symptoms daily and consider hospitalization. 
- Obtain Neurology consult, and initiate evaluation. 
- Consider, as necessary, discussing with the study 
physician. 
- If clinical course is rapidly progressive (particularly 
if difficulty breathing and/or trouble swallowing), 
promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant  
- If clinical course is not rapidly progressive, start 
systemic steroids (e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no improvement within 3 to 
5 days, continue additional work up and start 
treatment with IV methylprednisolone 2 to 
4 mg/kg/day 
- If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 
days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
- Once the patient is improving, gradually taper 
steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals, or anti-PJP treatment (refer to 
current NCCN guidelines for treatment of cancer-
related infections).a 
 
Grade 3 or 4 
(pain associated 
with severe 
For Grade 3: 
Hold study drug/study regimen 
dose until resolution to Grade ≤1. 
For Grade 3 or 4 (severe or life-threatening events): 
- Monitor symptoms closely; recommend 
hospitalization. 


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Appendix 4. Dosing Modification and Toxicity Management Guidelines for Specific Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
 
Grade of Event 
(NCI CTCAE v 4) 
Dose Modifications 
Toxicity Management 
weakness; limiting 
self-care ADLs) 
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade 
≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
- Obtain Neurology consult, and complete full 
evaluation. 
- Consider, as necessary, discussing with the study 
physician. 
- Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with receiving 
input from Neurology consultant. 
- If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 
days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
- Consider whether patient may require IV IG, 
plasmapheresis. 
- Once the patient is improving, gradually taper 
steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals, or anti-PJP treatment (refer to 
current NCCN guidelines for treatment of cancer-
related infections).a
a: ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
b: FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 
Abbreviations: AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST 
Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung 
disease; imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  
Magnetic resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly 
known as Pneumocystis carinii pneumonia); PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-
stimulating hormone; ULN Upper limit of normal.
 
 
 


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APPENDIX 5 
Appendix 6. Dosing Modification and Toxicity Management Guidelines for Infusion Related Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
- Manage per institutional standard at the discretion of 
investigator 
- Monitor 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 
Grade 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 
Grade 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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APPENDIX 7 
Appendix 8. Dosing Modification and Toxicity Management Guidelines for Non Immune-mediated Reactions for 
Durvalumab Monotherapy (17 October 2019 Version) 
Non-immune Mediated Reactions 
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 modifications  
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. 
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 should be based on accompanying clinical signs/symptoms, the 
Investigator’s clinical judgment, and in consultation with the sponsor-
investigator via the BTCRC project manager)  
Treat accordingly as per 
institutional standard  
 


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APPENDIX 5 
Guidelines During COVID-19 Pandemic or Other National Crisis 
The following changes may be implemented and/or adapted without causing a deviation during 
COVID-19 or other national crisis. HOWEVER, the usual protocol parameters must be 
reinstated when the emergency is over or whenever local authorities and policies permit. 
 
Subjects on active treatment: 
1. Treatment infusions and clinic visits may be delayed by maximum of 4 weeks from the 
date of expected visit if the safety of the subject is of concern. Any further delay should 
be entered as deviation and marked as due to COVID-19. 
2. Any subject on treatment who develops COVID-19 infection or complications due to 
COVID-19, should be captured as SAE/AE not related to treatment. Treatment should be 
temporarily held for those subjects due to lack of safety data in this situation. However, if 
a subject recovers and can restart study drug within the 12 week period per protocol, the 
sponsor investigator must be consulted prior to restarting. All subjects should be followed 
up per protocol (subjects who discontinue without progression). 
3. If subjects are unable to get labs and imaging done at the enrolling Institution, these may 
be performed locally but must be reviewed by the treating physician. The enrolling 
Institution should make all effort to obtain the local imaging and it be re-read by a 
radiologist at enrolling Institution. 
4. Telephone or telemedicine visits may be counted as a clinic visit. Physical exam, 
including vitals (for clinic note), may be marked as missed provided that the treating 
physician has done a thorough interim history and determines there probably would not 
be any significant change in exam. These will NOT be counted as deviations but MUST 
be captured as limited PE due to COVID-19. 
5. Imaging and cystoscopy: 
a. Disease imaging: may be delayed by 4 -6 weeks based on subject safety and will 
NOT be captured as a deviation. If the imaging needs to be further delayed, please 
consult the sponsor investigator; these delays should be entered as deviations due to 
COVID-19. 
b. Cystoscopy: may be delayed by 4-6 weeks based on subject safety and will NOT be 
captured as a deviation. If the cystoscopy needs to be further delayed, please consult 
the sponsor investigator; these delays should be entered as deviations due to COVID-
19. 
 
Subjects on Follow up: 
1. Subjects who have not had disease progression: Follow up visits including imaging and 
cystoscopy may be delayed by 1-2 months, depending upon the need to maintain safety. 
Any further delay should be captured as a deviation related to COVID-19. Telemedicine 
or telephone visits will be allowed without physical exam and vitals. See #5 above. 
2. Subjects who are being followed for survival: Survival follow up may be done via 
telephone or may be obtained from clinic/telemedicine note, etc. when possible. 
3. Any subject who develops COVID-19 infection should be captured as SAE/AE not 
related to treatment. 
 
 


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COVID-19 Guidelines from AstraZeneca (23 April 2020) 
In relation to the current outbreak of COVID-19 disease, AstraZeneca is providing guidance to 
investigators and treating physicians on the management of patients taking durvalumab and/or 
tremelimumab as part of a clinical trial based on our current understanding of the scientific data 
and the known safety profile of durvalumab/tremelimumab. We are closely monitoring the 
emerging literature and adverse event reports to continually assess this position in the light of 
new information and will provide updated information if this position changes.  
 
Risk of pneumonitis associated with the use of durvalumab and/or tremelimumab vs 
COVID-19  
Symptoms of durvalumab/tremelimumab-induced pneumonitis include fever, cough, shortness of 
breath, difficulty breathing and an abnormal chest scan. Please note that these symptoms are 
similar to symptoms of coronavirus pneumonia. Physicians should consider coronavirus 
infection and other infectious and non-infectious etiologist versus symptoms suggestive of 
pneumonitis. A thorough evaluation should be performed to accurately identify the underlying 
pathology.  
 
Since current knowledge about COVID-19 infection is limited, please review available literature 
that could be a useful aid when considering diagnosis and treatment options. A case-by-case 
assessment of the benefit/risk balance for an individual patient should be done for decisions on 
discontinuing or pausing treatment.  
 
To help ensure patient safety, please confirm that all site personnel involved in one or more 
studies involving durvalumab and/or tremelimumab familiarize themselves with the pneumonitis 
monitoring and management guidelines in the protocol. 
 
Patients should be reminded that, if a potential exposure to COVID-19 is suspected, they should 
notify health authorities and medical personnel of their participation in a study on a drug with 
known risk of pneumonitis. If a patient exhibits symptoms consistent with those of either drug-
induced pneumonitis or COVID-19, it is recommended that she/he should be advised to contact 
both the recommended COVID-19 point of contact (as per local guidance), as well as her/his 
investigator/oncologist by phone. 
 
Risk of COVID-19 severity associated with the use of durvalumab and/or tremelimumab  
To date, it is unknown whether durvalumab and/or tremelimumab can increase the risk of 
severity of COVID-19. We are in the process of gathering the data to better understand the risk 
or severity in the context of COVID-19. In addition, we are in the process of gathering the data 
on the effect of durvalumab/tremelimumab on the immune response to viruses like COVID-19.  
 
Suspected/Confirmed COVID-19  
 New Patients: For potential participants who are exhibiting symptoms consistent with 
COVID-19 or have tested positive, these patients are recommended, following your 
medical assessment, to not be enrolled in the study until their symptoms have resolved.  
 Ongoing Patients: For patients who are exhibiting symptoms consistent with COVID-19, 
study medication can be continued if feasible and if considered medically appropriate by 
your criteria. 
 
 


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