Clinical trial NCT02901548
Conditions: Carcinoma in Situ of Bladder Bladder Cancer
Keywords: BCG refractory CIS Urothelial CIS of bladder Carcinoma in situ (CIS) Bacillus Calmette-Guérin (BCG) Medi4736 Durvalumab CIS of the bladder Bladder cancer BCG Vaccine Bladder diseases Urothelial diseases
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2017-02-16; Completion date: 2021-09-07
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test if an experimental drug called Durvalumab (Medi4736) given by intravenous (IV) infusion is effective in treating carcinoma in situ (CIS) of the bladder that no longer responds to Bacillus Calmette-Guérin (BCG) and to collect information on the safety of these drugs and whether they cause any side effects.

Detailed description:

Arms: arm 1: Durvalumab: Fixed dose level IV infusion every 4 weeks for 13 study treatment cycles/infusions over 12 months/1 year. Cystoscopy with biopsy will be performed every 3 months to monitor the treatment response during this one year of treatment phase. It will be performed every 6 months during year 2 of the surveillance phase.
Interventions: intervention 1: Durvalumab intervention 2: Cystoscopy with Biopsy
Intervention descriptions: intervention 1: Durvalumab will be given every 4 weeks at 1500 mg/kg IV for total of 12 months/13 doses. intervention 2: Cystoscopy with biopsy and transurethral resection of the bladder tumor (TURBT) (if indicated) will be performed at baseline, month 3, 6, 9, 12, 18, and 24. The month 6 and 24 cystoscopy will be done in the operating room with mapping biopsy. Rest of the cystoscopic exam with biopsy will be performed in the out-patient office setting and if clinically indicated will be repeated in the operating room. Participants will be off study if any of the biopsies document muscle invasive (T2 or above) urothelial carcinoma. Participants will also be off study if their month 6, 9, 12, 18 biopsies show persistent (month 6) or recurrent CIS or invasive (T1 or above) urothelial carcinoma. Otherwise, participants will remain on study until after the month 24 mapping biopsy.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Phase 2 Study of Check Point Inhibitor, Durvalumab (MEDI4736) for Bacillus 
Calmette-Guérin (BCG) Refractory Urothelial Carcinoma in Situ (CIS) of the 
Bladder 
NCT02901548 
 
Version 1.9.4 
June 12, 2019 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 1 of 113 
 
Investigational Drug 
Substance(s) 
Durvalumab (Medi4736)  
Study Number 
MCC18788/ESR-15-11326 
Version Number 
1.9.4 
Date 
06/12/2019 
A phase 2 study of check point inhibitor, Durvalumab (MEDI4736) 
for bacillus Calmette-Guérin (BCG) refractory urothelial carcinoma 
in situ (CIS) of the bladder 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 2 of 113 
 
STUDY PERSONNEL 
 
Sponsor: 
 
H Lee Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 33612 
 
Study Location: 
 
H. Lee Moffitt Cancer Center and Research Institute 
 
Principal Investigator: 
 
Jingsong Zhang, M.D., Ph.D.  
12902 Magnolia Dr. 
Tampa, FL  33612 
Tel: 813 745 1363 
Fax: 813 745 8494 
Email: jingsong.zhang@moffitt.org 
 
 
Co-Investigators 
 
Wade Sexton, M.D., Scott Gilbert M.D., Michael Poch, 
M.D., Julio Pow-Sang, M.D., Philippe Spiess M.D.  
 
Biostatistician 
Youngchul Kim, Ph.D 
 
 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 3 of 113 
 
 
PROTOCOL SYNOPSIS 
Clinical Protocol: MCC18788/ ESR-15-11326 
Study Title:  A phase 2 study of check point inhibitor, Durvalumab (MEDI4736) for Bacillus 
Calmette-Guérin (BCG) refractory urothelial carcinoma in situ (CIS) of the bladder 
Protocol Number:  MCC18788/ ESR-15-11326 
Clinical Phase:  phase 2 
Study Duration:   3-4 years 
Investigational Product(s) and Reference Therapy: 
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a 
concentration of 50 mg/mL for intravenous (IV) administration. 
Research Hypothesis:  
Durvalumab will be effective in treating BCG refractory urothelial CIS of bladder 
Objectives: 
Primary Objectives: 
To evaluate whether Durvalumab can improve complete response rate at month 6 to 40% or 
higher  
Secondary Objective(s): 
To evaluate whether Durvalumab can improve the response rate at year 2 to 30% or higher  
To assess the safety and tolerability of Durvalumab at 1500 mg Q4W IV infusion for 12 months 
Exploratory Objective(s): 
• Correlate PD-L1 expression in urothelial carcinoma, tumor infiltrating T cells, 
mononuclear cells  in bladder biopsies or TURBT samples with response to Durvalumab 
• 
Correlate chromosomal abnormalities detected by UroVysion urine test with response to 
Durvalumab  
• 
Compare the tumor mutation burden and alterations in DNA repair genes in the pre and post 
Durvalumab urothelial bladder cancer samples  
Study Design: 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 4 of 113 
 
This is a multicenter, open-label, Phase 2 study of Durvalumab to evaluate its antitumor activity 
for BCG refractory urothelial carcinoma in situ (CIS) of the bladder.  Durvalumab will be given 
every 4 weeks at 1500 mg IV for total of 12 months. Cystoscopy with biopsy and TURBT (if 
indicated) will be performed at baseline, and every 3 months during the 12 months treatment 
period and then every 4 months in the 12 month surveillance period. Of note, cystoscopy at 
baseline, month 6, and 24 will be performed in the operating room with mapping biopsies.  
Patients will be off study if any of the biopsies document muscle invasive (T2 or above) 
urothelial carcinoma. Patients will also be off study if their month 6, 12, 16, 20, biopsies show 
persistent (month 6) or recurrent CIS or invasive (T1 or above) urothelial carcinoma. Otherwise, 
patients will remain on study until after the month 24 biopsy. 
 
Number of Centers: 2-3 centers in North America 
Number of Subjects: 34 
Study Population: 
Adult male or female subjects with pathologically confirmed urothelial carcinoma in situ (CIS) 
of the bladder that is refractory to BCG (see inclusion criteria 2).  
Inclusion Criteria: 
1. Age ≥ 18 years at the time of screening with life expectancy of ≥ 2 years 
2. Must have pathologically confirmed urothelial carcinoma in situ (CIS) of the bladder that 
meet one of the following criteria: 
1.        Persistence of high-grade CIS at 6 months following an adequate course of BCG; OR 
2.        Stage/grade progression at 3 months after induction BCG; OR 
3.        Recurrence of high-grade CIS after achieving a disease-free state (i.e., CR) following 
induction of an adequate course of BCG that occurs < 9 months after the last exposure to 
BCG; OR 
4.        Persistent CIS noted on the bladder biopsies within 3 months of completing at least 2 
induction BCG (minimum of five weekly instillations). 
An adequate course of BCG should be defined as at least one course of induction (minimum 
of five weekly instillations) and one  maintenance (two of three instillations) in a 6 months 
period, with an exception for any patient with grade/stage progression after induction BCG 
(minimum of five weekly instillations). 
 
3. ECOG performance status of 0-1. 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 5 of 113 
 
4. Adequate organ and marrow function, as defined as: 
- 
Hemoglobin ≥ 9.0 g/dL,  
- 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3), 
- 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
- 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal  
- 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: 
Males: 
 
 
Creatinine CL 
(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) 
 
5. Written informed consent and any locally required authorization (e.g., HIPAA in the USA) 
obtained from the subject prior to performing any protocol-related procedures, including 
screening evaluations. 
6. Female subjects must not be pregnant, or breast feeding and must have a negative urine or 
serum pregnancy test within 28 days prior to treatment on Day 1. Females of childbearing 
potential who are sexually active with a non-sterilized male partner must use a highly 
effective method of contraception from the time of screening, and must agree to continue 
using such precautions for 90 days after the final dose of Durvalumab. They must also 
refrain from egg cell donation for 90 days after the final dose of Durvalumab. 
7. Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use a highly effective method of contraception and  refrain from sperm donation from 
Day 1 through 90 days after receipt of the final dose of Durvalumab. 
 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 6 of 113 
 
 
Exclusion Criteria: 
1. 
Muscle invasive (T2 or above) urothelial carcinoma or urothelial carcinoma outside 
the bladder. 
2. 
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site) or previous enrolment in the present study. 
3. 
Participation in another clinical study with an investigational product during the last 4 
weeks. 
4. 
Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.  
5. 
History of another primary malignancy except for: 
• 
Malignancy treated with curative intent and with no known active disease ≥3years  
before the first dose of study drug and of low potential risk for recurrence. 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
• 
Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer 
in situ. 
6. 
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, tyrosine kinase inhibitor, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) ≤ 30 days prior to the first dose of 
study drug and within 6 weeks for nitrosourea, mitomycin C or intravesicle therapy). 
7. 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) 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 or above) from previous anti-cancer 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 7 of 113 
 
therapy.  
10. 
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any 
previous immunotherapy agent, or any unresolved irAE >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. 
12. 
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis). 
13. 
History of primary immunodeficiency. 
14. 
History of allogeneic organ transplant.  
15. 
History of pneumonitis. 
16. 
History of hypersensitivity to durvalumab or any excipient.  
17. 
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 with confirmed 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. 
18. 
Known history of previous clinical diagnosis of tuberculosis. 
19. 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab. 
20. 
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. 
21. 
Any condition that, in the opinion of the investigator, would interfere with evaluation 
of study treatment or interpretation of patient safety or study results. 
22. 
Subjects with uncontrolled seizures. 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 8 of 113 
 
23. 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, 
inclusive of but not limited to surgery, radiation and/or corticosteroids. 
Investigational Product(s), Dose and Mode of Administration: 
Durvalumab will be given at 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV infusion for 12 
months. Population PK analysis indicated only minor impact of body weight (WT) on PK of 
durvalumab (coefficient of ≤ 0.5). Please refer to fixed dose under 1.2.2 for details. 
 
Study Assessments and Criteria for Evaluation: 
Safety Assessments:  Adverse events and toxicity will be captured with CTCAE version 4.03. 
Based on the generally healthy condition of patients with stage 0is or stage I (with Cis 
component), we do not anticipate significant toxicities. The study will also be stopped early if 3 
or more subjects in the first 10 subjects developed SAEs attributed to Durvalumab. 
Efficacy Assessments: 
Complete response rate at month 6 as determined by mapping biopsy at month 6 during 
treatment with Durvalumab.  
Complete response rate at year 2 as determined by mapping biopsy at year 2 after 1 year of 
Durvalumab. 
Statistical Methods and Data Analysis: 
Statistical analysis for the primary and secondary endpoints will be descriptive. 
Sample Size Determination: The null hypothesis is the 18% historical complete response rate at 
month 6 will be tested against a one-sided alternative of 40% or higher complete response rate 
with Durvalumab at month 6 in BCG refectory CIS of bladder.  We use a Simon's two-stage 
design (Simon, 1989) based on the optimal two-stage designs and admissible designs (Jung et al. 
2004) for Phase II single arm clinical trials. The required total number of subjects is 34. 13 is the 
number of subjects accrued during stage 1. If 3 or fewer responses are observed during stage 1, 
the trial is stopped early for futility. If 9 or fewer responses of total 34 patients are observed by 
the end of stage two, then no further investigation of the drug is warranted. This design yields a 
one-sided type I error rate of 0.047 and power of 80% when the true response rate is 40% based 
on Simon’s optimal two-stage design. 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 9 of 113 
 
 
SCHEDULE OF STUDY ASSESSMENTS 
Schedule of study assessments: Screening and Treatment Period (<<12 months: maximum 
of 13 doses, last infusion week 50>>) 
 
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required in 
the management of 
the subject. 
 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline Every 4 weeks 
Every 3 months 
of 12 months 
treatment phase 
Every 4 
months of the 
12 months 
surveillance 
phase 
End of Trial 
visit 
Day 
 
-28 to -1 1 
Day 1 of the week 
Week 
 
-4 to -1 
0 
4, 8, 12,16, 20, 24, 28, 
32, 36, 40, 44, 48,  
 14, 26, 38, 52 
68, 86  104,  
105 
(± 3 days)                               (± 14 days) 
   (±14 days)             (±7 days) 
Written informed 
consent/assignment 
of  subject 
identification 
number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and 
history of tobacco 
and alcohol use 
 
X 
 
 
 
 
 
Previous treatments 
for CIS of bladder 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Formal verification 
of eligibility criteria 
 
X 
 
 
 
 
 
Hepatitis B and C; 
HIV 
 
X 
 
 
 
 
 
Urine hCG or serum 
βhCGb 
 
X 
As clinically indicated 
Durvalumab 
administration  
 
 
X 
X 
 
 
 
Clinic visit with 
history and physical 
examinationc 
 
X 
X 
X 
 
X 
X 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 10 of 113 
 
Schedule of study assessments: Screening and Treatment Period (<<12 months: maximum 
of 13 doses, last infusion week 50>>) 
 
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required in 
the management of 
the subject. 
 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline Every 4 weeks 
Every 3 months 
of 12 months 
treatment phase 
Every 4 
months of the 
12 months 
surveillance 
phase 
End of Trial 
visit 
Day 
 
-28 to -1 1 
Day 1 of the week 
Week 
 
-4 to -1 
0 
4, 8, 12,16, 20, 24, 28, 
32, 36, 40, 44, 48,  
 14, 26, 38, 52 
68, 86  104,  
105 
(± 3 days)                               (± 14 days) 
   (±14 days)             (±7 days) 
Vital signs (pre- 
during and post-
infusion vital signs 
assessments)d 
 
X 
X 
X 
X 
X 
X 
Electrocardiograme 
 
X 
X then 
as 
clinically 
indicated 
 
 
 
 
Adverse 
event/serious 
adverse event 
assessment 
 
X 
X 
All visits 
Concomitant 
medications 
 
X 
X 
All visits 
ECOG performance 
status 
 
X 
X 
X 
 
X 
 
Liver enzyme panelf  
 
 
X 
 
X 
 
Serum Chemistry 
(complete clin chem. 
panel including 
Liver enzymes, 
amylase and lipase)f 
 
X 
X 
X 
 
 
 
Thyroid function 
tests (TSH and fT3 
and fT4)g 
 
X 
X 
X 
 
X 
 
Hematologyf 
 
X 
X 
X 
 
X 
 
Urinalysish 
 
X 
 
X 
 
 
 
 


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 11 of 113 
 
Schedule of study assessments: Screening and Treatment Period (<<12 months: maximum 
of 13 doses, last infusion week 50>>) 
 
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required in 
the management of 
the subject. 
 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline Every 4 weeks 
Every 3 months 
of 12 months 
treatment phase 
Every 4 
months of the 
12 months 
surveillance 
phase 
End of Trial 
visit 
Day 
 
-28 to -1 1 
Day 1 of the week 
Week 
 
-4 to -1 
0 
4, 8, 12,16, 20, 24, 28, 
32, 36, 40, 44, 48,  
 14, 26, 38, 52 
68, 86  104,  
105 
(± 3 days)                               (± 14 days) 
   (±14 days)             (±7 days) 
Coagulation 
parametersi 
 
X 
As clinically indicted 
Cystoscopy with  
biopsyj 
 
X 
 
 
X 
X 
 
Urine cytology with 
UroVysion test 
 
X 
 
 
X at week 26 
X at week 104  
Tumor assessment 
(chest X-ray, 
abdominal pelvic 
CT)k 
 
X 
 
 
 
 
 
 
a Within the protocol could state if for that trial there is a minimum number of  subjects to be sampled 
b  Pre-menopausal female subjects of childbearing potential only 
c Full physical examination at baseline; targeted physical examination (including weight and vital signs) at other timepoints 
d Subjects will have their blood pressure and pulse measured before, during and after the infusion at the following times (based on 
a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
• 
In 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 then blood pressure and pulse measurements should be collected every 30 
minutes (±5 minutes) and as described above or more frequently if clinically indicated. 
e 
ECG during screening and at Day1 –baseline. There after as clinically indicated. Baseline and abnormal 
ECG at any time in triplicate others single. 1 ECG is needed while on treatment>>, and as clinically indicated.  ECGs should 
be taken within an hour prior to the start of the infusion and at least one time point 0 to 3 hours after the infusion.   
f 
If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 
1. Results for safety bloods must be available and reviewed before commencing an infusion. Gamma 
glutamyltransferase tested at Screening, Day 1 and as clinically indicated.    


Clinical Study Protocol: Durvalumab CIS of Bladder 
Drug Substance Durvalumab (Medi4736) 
Study Number: MCC 18788/ESR-15-11326 
Edition Number 1.9.4 
Date 06/12/2019 
 
Page 12 of 113 
 
g 
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. 
h 
Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated. 
i 
Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
j 
Cystoscopy at baseline, week 26/month 6, and week 104/month 24 will be performed in the operating room with 
mapping biopsies. The mapping biopsy at baseline can be waived if the subject has a cystoscopy within 8 weeks, which 
documented recurrent or persistent CIS without evidence of muscle invasive urothelial bladder cancer. After month 3, 
9, 12, 16 and 20 cystoscopy,  a biopsy will be performed at the discretion of the Urologist. 
k 
Chest X-ray and CT (preferably with IV contrast) are collected during screening (for baseline) to rule out metastatic 
disease and secondary malignancy, Due to the low risk of metastasis with CIS of bladder, repeat imaging studies will 
not be indicated until cancer in the bladder has progressed to the muscle invasive stage. At this point subjects will be 
off study due to disease progression 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 13 of 113 
 
TABLE OF CONTENTS 
                                          PAGE 
SYNOPSIS ............................................................................................................... 3 
SCHEDULE OF ASSESSMENTS .......................................................................... 9 
TABLE OF CONTENTS ....................................................................................... 13 
ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 19 
1. 
INTRODUCTION ................................................................................................. 24 
1.1 
Disease Background ............................................................................................... 24 
1.2 
Durvalumab Background ....................................................................................... 25 
1.2.1 
Summary of non-clinical experience ..................................................................... 25 
1.2.2 
Summary of clinical experience ............................................................................. 27 
1.3 
Research hypothesis ............................................................................................... 31 
1.4 
Rationale for conducting this study ....................................................................... 31 
1.5 
Benefit/risk and ethical assessment........................................................................ 32 
2. 
STUDY OBJECTIVES .......................................................................................... 33 
2.1 
Primary objective(s) ............................................................................................... 33 
2.2 
Secondary objective(s) ........................................................................................... 33 
2.3 
Exploratory objective(s) ......................................................................................... 33 
3. 
STUDY DESIGN ................................................................................................... 33 
3.1 
Overview of study design ...................................................................................... 33 
3.2 
Study schema ......................................................................................................... 34 
3.3 
Study Oversight for Safety Evaluation .................................................................. 36 
4. 
SUBJECT SELECTION ........................................................................................ 36 
4.1 
Inclusion criteria .................................................................................................... 36 
4.2 
Exclusion criteria ................................................................................................... 37 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study ................................ 40 
4.4 
Replacement of subjects ........................................................................................ 41 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................... 41 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 14 of 113 
 
5.1 
Durvalumab ............................................................................................................ 41 
5.1.1 
Formulation/packaging/storage .............................................................................. 41 
5.1.2 
Durvalumab Doses and treatment regimens .......................................................... 41 
5.1.3 
Study drug preparation ........................................................................................... 42 
5.1.4 
Monitoring of dose administration ......................................................................... 43 
5.1.5 
Accountability and dispensation ............................................................................ 44 
5.1.6 
Disposition of unused investigational study drug .................................................. 44 
6. 
TREATMENT PLAN ............................................................................................ 45 
6.1 
Subject enrollment  ................................................................................................ 45 
6.2 
Dosage and Administration .................................................................................... 45 
6.3 
Dose Modification and Toxicity Management ...................................................... 45 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) .................................................................................................. 47 
7.1 
Restrictions during the study ................................................................................. 47 
7.2 
Concomitant treatment(s) ....................................................................................... 48 
7.2.1 
Permitted concomitant medications ....................................................................... 48 
7.2.2 
Excluded Concomitant Medications ...................................................................... 48 
8. 
STUDY PROCEDURES ....................................................................................... 49 
8.1 
Schedule of study procedures ................................................................................ 49 
8.1.1 
Screening Phase ..................................................................................................... 49 
8.1.2 
Treatment Phase ..................................................................................................... 50 
8.1.3 
End of Treatment ................................................................................................... 50 
8.2 
Description of study procedures ............................................................................ 51 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and 
vital signs ............................................................................................................... 51 
8.2.2 
Clinical laboratory tests ......................................................................................... 52 
8.3 
Biological sampling procedures ............................................................................. 54 
9. 
DISEASE EVALUATION AND METHODS ...................................................... 58 
9.1.1 
Pathological response ............................................................................................. 60 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 15 of 113 
 
9.1.2 
Urine cytology and UroVysion test ....................................................................... 60 
10. 
ASSESSMENT OF SAFETY ................................................................................ 59 
10.1.1 
Safety Parameters ................................................................................................... 59 
10.1.1.1 Definition of adverse events .................................................................................. 59 
10.1.2 
Definition of serious adverse events ...................................................................... 60 
10.1.3 
Definition of adverse events of special interest (AESI) ......................................... 60 
10.1.4 
Pneumonitis ............................................................................................................ 61 
10.1.5 
Hypersensitivity Reactions .................................................................................... 61 
10.1.6 
Hepatic function abnormalities (hepatotoxicity) ................................................... 62 
10.1.7 
Gastrointestinal disorders ....................................................................................... 62 
10.1.8 
Endocrine disorders ............................................................................................... 63 
10.1.9 
Pancreatic disorders ............................................................................................... 63 
10.1.10 
Neurotoxicity ......................................................................................................... 63 
10.1.11     Nephritis………………………………………………………………………….63 
10.2 
Assessment of safety parameters ........................................................................... 64 
10.2.1 
Assessment of severity ........................................................................................... 64 
10.2.2 
Assessment of relationship .................................................................................... 65 
10.3 
Recording of adverse events and serious adverse events ....................................... 65 
10.3.1 
Study recording period and follow-up for adverse events and serious 
adverse events ........................................................................................................ 66 
10.3.2 
Reporting of serious adverse events....................................................................... 67 
10.3.3 
Reporting of deaths ................................................................................................ 68 
10.3.4 
Other events requiring reporting ............................................................................ 69 
10.3.5 
Overdose ................................................................................................................ 69 
10.3.6 
Hepatic function abnormality ................................................................................ 69 
10.3.7 
Pregnancy ............................................................................................................... 70 
10.3.8 
Maternal exposure .................................................................................................. 70 
10.3.9 
Paternal exposure ................................................................................................... 71 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 71 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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11.1 
Description of analysis sets .................................................................................... 71 
11.1.1 
Safety analysis set .................................................................................................. 71 
11.1.2 
Efficacy analysis set ............................................................................................... 71 
11.2 
Methods of statistical analyses ............................................................................... 72 
11.2.1 
Safety Analyses ...................................................................................................... 72 
11.2.2 
Efficacy Analyses .................................................................................................. 73 
11.2.3 
Exploratory Analyses ............................................................................................. 73 
11.2.4 
Interim analyses ..................................................................................................... 73 
11.3 
Determination of sample size ................................................................................. 73 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 73 
12.1 
Ethical conduct of the study ................................................................................... 73 
12.2 
Ethics and regulatory review.................................................................................. 74 
12.3 
Informed consent ................................................................................................... 74 
12.4 
Changes to the protocol and informed consent form ............................................. 75 
12.5 
Audits and inspections ........................................................................................... 75 
13. 
STUDY MANAGEMENT .................................................................................... 75 
13.1 
Training of study site personnel ............................................................................. 75 
13.2 
Monitoring of the study ......................................................................................... 75 
13.3 
Study timetable and end of study ........................................................................... 76 
13.4         Affiliate Sites Required Documentation………………………………….. 
14. 
DATA MANAGEMENT ....................................................................................... 77 
14.1         Data Management and Monitoring/Auditing…………………………….. 
14.2 
Study governance and oversight ............................................................................ 77 
15. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 78 
15.1 
Identity of investigational product(s) ..................................................................... 78 
16. 
LIST OF REFERENCES ....................................................................................... 78 
 
 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 17 of 113 
 
LIST OF TABLES 
Table 1  
Dose Modifications and Toxicity Management Guidelines for 
Immune-Mediated Reactions Associated with Durvalumab  ................... 82 
Table 2  
Dosing Modifications and Toxicity Management Guidelines for 
Infusion-Related Reactions Associated With Durvalumab  ................... 102 
Table 3  
Dosing Modifications and Toxicity Management Guidelines for 
Non-immune Mediated Reactions Associated With Durvalumab ......... 103 
Table 4  
Effective methods of contraception (two methods must be used) ............ 47 
Table 5  
Prohibited and Rescue Medications  ........................................................ 49 
Table 6 
Hematology Laboratory Tests  ................................................................. 53 
Table 7  
Clinical chemistry (Serum or Plasma) Laboratory Tests  ........................ 53 
Table 8  
Urinalysis Tests  ....................................................................................... 53 
Table 9  
List of investigational products for this study  ......................................... 78 
  
LIST OF FIGURES 
Figure 1  
 Study flow chart  ...................................................................................... 35 
 
LIST OF APPENDICES 
Appendix A  
Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 Monotherapy 
or Combination therapy with Tremelimumab or Tremelimumab monotherapy) November2017 
Version ………………………………………………………………………………..82 
Appendix B 
Durvalumab Dose Calculations …………………………………………103 
Appendix C 
Schedule of study procedures: follow-up for subjects who have completed 
durvalumab treatment and achieved disease control (until confirmed 
progression of disease) and subjects who have discontinued durvalumab 
due to toxicity in the absence of confirmed progression of disease……..105 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 18 of 113 
 
Appendix D 
Schedule of study procedures: follow-up for subjects who have 
discontinued durvalumab treatment due to confirmed progression of disease 
at the investigator discretion …………………………………………..106 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 19 of 113 
 
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 
CIS 
Carcinoma in situ 
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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 20 of 113 
 
Abbreviation or 
special term 
Explanation 
DC 
disease control 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DMC 
Data monitoring committee 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
disodium edetate dihydrate 
Fc 
fragment crystallizable 
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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 21 of 113 
 
Abbreviation or 
special term 
Explanation 
IGSF 
immunoglobulin superfamily 
IHC 
immunohistochemistry  
IL 
interleukin 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
MAb 
monoclonal antibody 
MDSC 
Myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
micro ribonucleic acid 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 22 of 113 
 
Abbreviation or 
special term 
Explanation 
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 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 23 of 113 
 
Abbreviation or 
special term 
Explanation 
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 the bladder tumor 
ULN 
upper limit of normal 
USA 
United States of America 
WFI 
water for injection 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 24 of 113 
 
1. 
INTRODUCTION 
1.1 
Disease Background 
Bladder cancer is the fifth most common cancer in the United States. Approximately 74,690 
new cases (56,390 men and 18,300 women) and 15,580 deaths (11,170 men and 4,410 
women) from bladder cancer would occur in the United States in 2014. Nearly 75% of newly 
diagnosed bladder cancers are non-muscle invasive bladder cancer (NMIBC) or “superficial 
bladder cancer”. CIS is a flat high-grade noninvasive urothelial carcinoma (UC) that has a 
high propensity for invasion and metastasis. It may occur in isolation or with a synchronous 
UC. Other than bladder, it could also occur in urothelium lines upper tract, prostatic and 
penile uretheral. The incidence of CIS of bladder is about 14-19% based on the published data 
with multiple bladder biopsies.  
Intravesical BCG remains the most effective treatment for non-muscle invasive bladder 
cancer. Its efficacy is attributed to immune response induced by BCG, which tends to wane 
over time. BCG refractory bladder cancer is commonly defined as recurrence after 2 induction 
courses of BCG, or recurrence within 6 months of completing induction and maintenance 
phase of BCG.  Unlike TURBT for Ta and T1 UC, CIS cannot be completely resected by 
biopsy. Standard therapy for BCG refractory CIS is radical cystectomy. For patients who are 
unsuitable for or refuse radical cystectomy, one approach would be enhancing the protective 
immunity induced by intravesical BCG by adding agents like interferon-α (Lam et al, 2003). 
Alternative approaches would be intravesical valrubicin or intravesical gemcitabine. Although 
intravesical valrubicin is the only FDA approved salvage agent, its complete response rate was 
only 18% at 3 months and 4% at year 2 in BCG refractory or intolerant CIS (Dinney et al, 
2013). There is an unmet need to develop more effective therapy for BCG refractory CIS of 
bladder. Based on the report of the FDA and AUA joint workshop in 2013, an agent with an 
initial CR rate of 40-50% at month 6 and a durable response rate of at least 30% would be 
considered meaningful for BCG refractory CIS (Jarow et al, 2014). 
Immune responses directed against tumors are one of the body’s natural defences against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 
attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver 
inhibitory signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such 
protein, and is upregulated in a broad range of cancers with a high frequency, with up to 88% 
expression in some tumor types. In a number of these cancers, including lung (Mu et al, 
2011), renal (Thompson et al, 2005; Thompson et al, 2006; Krambeck et al, 2007), pancreatic 
(Nomi et al, 2007; Loos et al, 2008; Wang et al, 2010), ovarian cancer (Hamanishi et al, 
2007), and hematologic malignancies (Andorsky et al, 2011; Brusa et al, 2013)  tumor cell 
expression of PD-L1 is associated with reduced survival and an unfavorable prognosis. 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help 
regulate normal immune responses and is utilized by tumors to help evade detection and 
elimination by the host immune system tumor response. In the lymph nodes, PD-L1 on 
antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an inhibitory 
signal to the T cell (Keir et al, 2008; Park et al, 2010). This results in reduced T-cell activation 
and fewer activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed 
on tumor cells binds to PD-1 and CD80 on activated T cells reaching the tumor. This delivers 
an inhibitory signal to those T cells, preventing them from killing target cancer cells and 
protecting the tumor from immune elimination (Zou and Chen, 2008). 
Previous immunohistochemistry study reported that 45% of CIS expressed PD-L1, which is 
the highest among different T stages of urothelial carcinoma of the bladder (Inman et al, 
2007). In 11 of 12 patients failing BCG treatment, PD-L1 expression was found to be 
extremely abundant in the BCG-induced bladder granulomata. More recently targeting PD-L1 
with MPDL3280A reported activity in metastatic urothelial bladder cancer tumours. The 
response rate is particularly high in tumours with PD-L1-positive tumour-infiltrating immune 
cells (Powles et al, 2014). These data support targeting PD-L1 in BCG refractory CIS 
urothelial bladder cancer. 
1.2 
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.  
1.2.1 Summary of non-clinical experience 
Non-clinical experience with durvalumab is fully described in the current version of the 
durvalumab Investigator’s Brochure (Version 12.0) 
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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 26 of 113 
 
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 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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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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. 
1.2.2 Summary of clinical experience 
Clinical experience with durvalumab is fully described in the current version of the 
durvalumab Investigator’s Brochure (Version 12.0). 
As of the DCO dates (15Apr2015 to 12Jul2015, Durvalumab IB Version 9.0), a total of 
1,883 subjects have been enrolled and treated in 30 ongoing durvalumab clinical studies, 
including 20 sponsored and 10 collaborative studies. Of the 1,883 subjects, 1,279 received 
durvalumab monotherapy, 440 received durvalumab in combination with tremelimumab or 
other anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 150 have 
been treated with blinded investigational product. No studies have been completed or 
terminated prematurely due to toxicity. 
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. 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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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-related 
AEs (irAEs), 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. 
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 (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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 29 of 113 
 
severity and resolved with or without sequelae. AEs that resulted in permanent discontinuation 
of durvalumab were considered as treatment related in 18 subjects (2.6%), with colitis being 
the most frequent treatment-related AE resulting in discontinuation (3 subjects). A majority of 
the treatment-related AEs resulting in discontinuation of durvalumab were ≥ Grade 3 in 
severity and resolved with or without sequelae.  
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in 
Study CD-ON-durvalumab-1108 
is 
generally 
consistent 
with 
that 
of 
Study D4191C00003/ATLANTIC in subjects with locally advanced or metastatic non-small-
cell lung cancer (NSCLC) treated with durvalumab 10 mg/kg Q2W. As of 05May2015, 264 of 
303 subjects (87.1%) reported any AE in Study D4191C00003/ATLANTIC. Overall, events 
reported in ≥ 10% of subjects were dyspnea (18.8%), fatigue (17.8%), decreased appetite 
(17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), and nausea (11.2%). Nearly two-
thirds of the subjects experienced AEs that were Grade 1 or 2 in severity and manageable by 
general treatment guidelines as described in the current durvalumab study protocols. Grade 3 
or higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 subjects (42.2%) 
reported AEs that were considered by the investigator as related to investigational product. 
Treatment-related AEs (all grades) reported in ≥ 2% of subjects were decreased appetite 
(6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, 
hyperthyroidism, hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased 
(2.3%); and vomiting (2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects were 
pneumonitis (3 subjects) and increased GGT (2 subjects). There was no treatment-related 
Grade 4 or 5 AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that occurred 
in ≥ 1.0% of subjects were dyspnea (6.6%); pleural effusion, general physical health 
deterioration (2.3% each); pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% each); 
and pneumonitis, respiratory failure, disease progression (1.0% each). Nine subjects had an 
SAE considered by the investigator as related to durvalumab. Each treatment-related SAE 
occurred in 1 subject each with the exception of pneumonitis, which occurred in 3 subjects. 
Fifteen of 303 subjects (5.0%) have died due to an AE (pneumonia [3 subjects]; general 
physical health deterioration, disease progression, hemoptysis, dyspnea [2 subjects each]; 
pulmonary sepsis, respiratory distress, cardiopulmonary arrest [verbatim term (VT)], hepatic 
failure, and sepsis [1 subject each]). None of these events was considered related to 
durvalumab. Twenty-three of 303 subjects (7.6%) permanently discontinued durvalumab 
treatment due to AEs. Events that led to discontinuation of durvalumab in ≥ 2 subjects were 
dyspnea, general physical health deterioration, and pneumonia. Treatment-related AEs that led 
to discontinuation were increased ALT and increased hepatic enzyme, which occurred in 1 
subject each. 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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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 (SD) in 4 subjects (19.0%); and progressive disease (PD) in 
5 subjects (23.8%). The remaining 8 subjects (38.1%) did not meet the criteria for complete 
remission (CR), mCR, partial remission (PR), SD, or PD at the date of assessment. 
Study CD-ON-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%.  
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 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A 
total of 1000 patients were simulated using body WT distribution of 40–120 kg. Simulation 
results demonstrate that body WT-based and fixed dosing regimens yield similar median 
steady state PK concentrations with slightly less overall between-subject variability with fixed 
dosing regimen.   
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 
2012, Narwal et al 2013]. Wang and colleagues investigated 12 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better 
for 7 of 12 antibodies [3]. In addition, they investigated 18 therapeutic proteins and peptides 
and showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-
subject variability in pharmacokinetic/pharmacodynamics parameters [Zhang et al 2012].  
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 
kg, a fixed dose of 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) is included in the current study. Fixed dosing of 
durvalumab is recommended only for subjects with > 30kg body weight due to endotoxin 
exposure.  Patients with a body weight less than or equal to 30 kg should be dosed using a 
weight-based dosing schedule (Appendix B).  
 
1.3 
Research hypothesis 
The null hypothesis that the 18% historical complete response rate at month 6 will be 
improved to 40% or higher with Durvalumab at month 6 in BCG refectory CIS of bladder.  
Such hypothesis is supported by the high percentage of PD-L1 IHC positivity in CIS of 
urothelial bladder cancer and enrichment of PD-L1 expression in the BCG-induced bladder 
granulomata after BCG failure (Inman et al, 2007). Vascular inflammation induced by bladder 
mapping biopsy would facilitate the deposition of immune complex containing durvalumab 
(Investigator brochure) at the biopsy sites. 
1.4 
Rationale for conducting this study 
There is an unmet need to develop more effective therapy for BCG refractory CIS of bladder. 
To facilitate drug development in this disease setting, FDA and AUA held a joint workshop in 
2013. Based on the report from this workshop, an agent with an initial CR rate of 40-50% at 
month 6 and a durable response rate of at least 30% would be considered meaningful for BCG 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 32 of 113 
 
refractory CIS. Response rate at month 6 is chosen as the primary endpoint. The historical 
18% month 6 complete response rate will be tested against a one-sided alternative of 
druvalumab treated patients would show a complete response rate 40% or higher.  Response 
rate at year 2 as well as safety assessments was chosen as secondary objectives. 
Durvalumab will be given at 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV infusion for 12 
months. Population PK analysis indicated only minor impact of body weight (WT) on PK of 
durvalumab (coefficient of ≤ 0.5). A fixed dosing approach is preferred due to ease of use and 
reduced dosing errors. 
1.5 
Benefit/risk and ethical assessment 
As described in section 1.2.2, Durvalumab is well tolerated in human subjects. No tumor types 
appeared to be associated with unique AEs. Immune-related AEs (irAEs), 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. These irAEs are not that different than the anti-
PD1or anti-PDL1 agents being approved by FDA for treating melanoma, kidney cancer and 
non-small cell lung cancer. 
Due to the lack of effective intravesical treatment for BCG refractory urothelial carcinoma in 
situ (CIS) of the bladder, radical cystectomy is often recommended. If subject’s CIS of 
bladder does not respond to IV Durvalumab, delaying cystectomy could lead to cancer 
progression to the muscle invasive or even metastatic stage. The protocol therefore mandates a 
baseline staging work up prior to study enrollment and every 3 months cystoscopy with 
mapping biopsy during the 2 year study period. For subjects who elect bladder preservation 
for their CIS of bladder, it is a common practice to do every 3 months surveillance cystoscopy 
till at least a year after completing the intravesical therapy.  We don’t anticipate adding IV 
Durvalumab will increase the risks or complications of routine cystoscopy with mapping 
biopsy. For subjects whose CIS of bladder responded Durvalumab, Durvalumab may provide 
an alternative treatment that leads to bladder preservation.  


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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2. 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
The primary objective of this study is to evaluate whether Durvalumab can improve complete 
response rate at month 6 to 40% or above based on the week 26 mapping biopsy in BCG 
refractory CIS urothelial bladder cancer 
 
2.2 
Secondary objective(s) 
1. To evaluate whether Durvalumab can improve the complete response rate  at year 2 to 
30% or above based on the week 104 mapping biopsy in BCG refractory CIS urothelial 
bladder cancer 
2. To assess the safety and tolerability of Durvalumab at 1500 mg Q4W IV infusion for 12 
months for BCG refractory CIS urothelial bladder cancer 
 
2.3 
Exploratory objective(s) 
1. Correlate PD-L1 expressions in urothelial carcinoma, tumor infiltrating  T cells, 
mononuclear cells  in bladder biopsy or TURBT samples with response to Durvalumab 
2. Correlate chromosomal abnormalities detected by UroVysion urine test with response to 
Durvalumab 
3. Compare the tumor mutation burden and alterations in DNA repair genes in the pre and post 
Durvalumab urothelial bladder cancer samples 
 
3. 
STUDY DESIGN 
3.1 
Overview of study design 
This is a multicenter, open-label, Phase 2 study of Durvalumab to evaluate its antitumor 
activity for BCG refractory urothelial carcinoma in situ (CIS) of the bladder.  We use a 
Simon's two-stage design (Simon, 1989) based on the optimal two-stage designs and 
admissible designs (Jung et al. 2004) for Phase II single arm clinical trials. In the first stage of 
this study plan, 13 patients will be accrued. If there are 3 or fewer responses in these 13 
patients, the study will be stopped. Otherwise, 21 additional patients will be accrued for a total 
of 34. Durvalumab will be given every 4 weeks at 1500 mg IV for total of 12 months/13 
doses. Cystoscopy with mapping biopsy and TURBT (if indicated) will be performed at 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 34 of 113 
 
baseline, month 6, and 24. Urine cytology with UroVysion test will be performed at baseline, 
month 6, and 24.  Patients will be off study if any of the biopsies documented muscle invasive 
(T2 or above) urothelial carcinoma. Patients will also be off study if their month 6, 12, 18 
biopsies showed persistent (month 6) or recurrent CIS or invasive (T1 or above) urothelial 
carcinoma. Otherwise, patient will remain on study until after the month 24 biopsy. 
 
Historical controls will be used to assess the efficacy of Durvalumab.  For exploratory 
analysis on PD-L1 expression, PD-L1 IHC will be performed with the SP263 antibody 
developed by Ventana. IHC positivity (either on tumor cells and/or infiltrating immune cells) 
will be assessed on the available mapping biopsy and or TURBT samples at time points 
defined in SCHEDULE OF STUDY ASSESSMENT. 
Data Monitoring Committee (DMC) at Moffitt Cancer Center will monitor this phase 2 study 
initiated by Moffitt’s investigator. 
3.2 
Study schema 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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Figure 1. Study flow chart 
 
 
 
 
 
 
 
 
Screening 
/enrolment 
Durvalumab 1500mg IV q4wk x 13 
doses 
Cystoscopy with biopsies every 3 
months  
Assess response based on month 6 
mapping biopsies 
 
Cystoscopy 
with biopsies 
every 4 months 
 
Response 
rate at 
month 24 
mapping 
biopsy 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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3.3 
Study Oversight for Safety Evaluation 
DMC at Moffitt Cancer Center will monitor this phase 2 study initiated by Moffitt’s investigator. The 
study will be stopped early if there are 3 or fewer responses in the first 13 patients in the stage I 
of Simon 2 stage design. The study will also be stopped early if 3 or more subjects of the first 
10 subjects developed SAEs attributed to Durvalumab. 
4. 
SUBJECT SELECTION  
4.1 
Inclusion criteria 
For inclusion in the study subjects must fulfill all of the following criteria: 
1. Age ≥ 18 years at the time of screening. 
2. Must have pathologically confirmed urothelial carcinoma in situ (CIS) of the bladder 
and meet one of the following criteria. 
1. Persistence of high-grade CIS at 6 months following an adequate course of BCG; 
OR 
2. Stage/grade progression at 3 months after induction BCG; OR 
3. Recurrence of high-grade CIS after achieving a disease-free state (i.e., CR) 
following induction of an adequate course of BCG that occurs < 9 months after the 
last exposure to BCG; OR 
4. Persistent CIS noted on the bladder biopsies within 3 months of completing at least 
2 induction BCG (minimum of five weekly instillations). 
An adequate course of BCG should be defined as at least one course of induction 
(minimum of five weekly instillations) and one  maintenance (two of three  
instillations ) in a 6 months period, with an exception for any patient with grade/stage 
progression after induction BCG (minimum of five weekly instillations). 
 
3. ECOG performance status of 0-1. 
4. Adequate organ and marrow function, as defined as: 
- 
Haemoglobin ≥ 9.0 g/dL, Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 
per mm3), and Platelet count ≥ 100 x 109/L (>100,000 per mm3) 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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- 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal Serum 
bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).   
- 
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance: 
Males: 
 
 
Creatinine CL 
(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) 
 
5. Written informed consent and any locally required authorization (e.g., HIPAA in the 
USA) obtained from the subject prior to performing any protocol-related procedures, 
including screening evaluations. 
6. Female subjects must not be pregnant, or breast feeding and must have a negative 
urine or serum pregnancy test within 28 days prior to treatment on day 1. Females of 
childbearing potential who are sexually active with a non-sterilized male partner must 
use a highly effective method of contraception from the time of screening, and must 
agree to continue using such precautions for 90 days after the final dose of 
Durvalumab. They must also refrain from egg cell donation for 90 days after the final 
dose of Durvalumab. 
7. Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a highly effective method of contraception and  refrain from sperm 
donation from Day 1 through 90 days after receipt of the final dose of Durvalumab. 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 38 of 113 
 
1. Muscle invasive (T2 or above) urothelial carcinoma or urothelial carcinoma outside 
the bladder. 
2. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site) or previous enrolment in the present study. 
3. Participation in another clinical study with an investigational product during the last 4 
weeks. 
4. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.  
5. History of another primary malignancy except for: 
- 
Malignancy treated with curative intent and with no known active disease ≥3 years 
before the first dose of study drug and of low potential risk for recurrence. 
- 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease. 
- 
Adequately treated carcinoma in situ without evidence of disease eg, cervical 
cancer in situ. 
6. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, tyrosine kinase inhibitor, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) ≤ 30 days prior to the first dose of 
study drug and within 6 weeks for nitrosourea, mitomycin C or intravesicle therapy). 
7. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) 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 or above) from previous anti-cancer therapy.  
<<Subjects with irreversible toxicity that is not reasonably expected to be exacerbated 
by the investigational product may be included (e.g., hearing loss, peripherally 
neuropathy)>>  


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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10. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >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. 
12. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis). 
13. History of primary immunodeficiency. 
14. History of allogeneic organ transplant.  
15. History of pneumonitis. 
16. History of hypersensitivity to durvalumab or any excipient.  
17. 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 with confirmed 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. 
18. Known history of previous clinical diagnosis of tuberculosis. 
19. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab. 
20. 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. 
21. Any condition that, in the opinion of the investigator, would interfere with evaluation 
of study treatment or interpretation of patient safety or study results. 
22. Subjects with uncontrolled seizures. 
23. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, 
inclusive of but not limited to surgery, radiation and/or corticosteroids. 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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4.3 
Withdrawal of Subjects from Study Treatment and/or Study 
Permanent discontinuation of Durvalumab 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
1. 
Withdrawal of consent or lost to follow-up 
2. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing. Patients with grade 3 toxicity at least possibly related to study drug will 
discontinue durvalumab.  Patients with prolonged grade 2 toxicity or who require dose 
delays for more than 2 weeks or require prolonged steroid use will discontinue 
durvalumab. 
3. 
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk 
4. 
Pregnancy or intent to become pregnant 
5. 
Any AE that meets criteria for discontinuation as defined in Appendix A 
6. 
Grade ≥ 3 infusion reaction 
7. 
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; eg, refusal to adhere to scheduled visits 
8. 
Initiation of alternative anticancer therapy including another investigational agent 
9. 
Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with durvalumab  
 
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment.  
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10.3.1 and Appendix C or D, including the collection of any 
protocol-specified blood specimens, unless consent is withdrawn or the subject is lost to 


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Drug Substance Durvalumab (Medi4736) 
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Edition Number 1.9.4 
Date 10/08/2018 
 
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follow-up or enrolled I another clinical study.  All subjects will be followed for survival.  
Subjects who decline to return to the site for evaluations will be offered follow-up by phone 
every 3 months as an alternative. 
 
Withdrawal of consent 
If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation.  
4.4 
Replacement of subjects 
Subjects withdrawn from the study prior to the month 6 /week 26 mapping biopsy will be 
replaced to ensure total of 34 evaluable subjects. Subjects who are incorrectly enrolled but are 
not yet initiated on treatment should be withdrawn from the study and replaced. 
5. 
INVESTIGATIONAL PRODUCT(S) 
5.1 
Durvalumab 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab to the investigator as a 500-mg vial solution for infusion after dilution. 
5.1.1 
Formulation/packaging/storage 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. 
The 
solution 
contains 
50 
mg/mL 
durvalumab, 
26 
mM 
histidine/ 
histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 
80; it has a pH of 6.0. The nominal fill volume is 10 mL.  Investigational product vials are 
stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Durvalumab must be used within 
the individually assigned expiry date on the label. 
5.1.2 
Durvalumab Doses and treatment regimens 
Treatment with fixed dose durvalumab at 1500 mg Q4W durvalumab (equivalent to 20 mg/kg 
Q4W, based on an average body WT of 75 kg) commences on Day 1 following confirmation 
of eligibility into the study and continues on a Q4W schedule for a maximum duration of 
treatment of 12 months (maximum of 13 doses).  Study treatment should be discontinued prior 
to 12 months if there is confirmed PD (unless the investigator considers the subject to 
continue to receive benefit from treatment), initiation of alternative cancer therapy, 


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unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue study 
treatment occur.   
Subjects who have a dose interruption due to toxicity at any point in the first 12 months of 
treatment may resume treatment and complete the 12-month treatment period. 
5.1.3 
Study drug preparation 
For patients weighing ≥ 30 kg, 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) 
(based on an average body WT of 75 kg) should be prepared. For subjects <30 kg body 
weight, 20 mg/kg dose should be prepared; dose is determined using body mass, calculating 
the stock volume of durvalumab to achieve the accurate dose according to Appendix B.   
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Infusion solutions must be allowed to equilibrate to room temperature prior to commencement 
of administration.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an 
IV bag containing 0.9% (w/v) saline with a final durvalumab concentration ranging from 1 to 
20 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter.  
Remove 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 (ie, 15.0 mL for 750 mg or 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. 


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Drug Substance Durvalumab (Medi4736) 
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Edition Number 1.9.4 
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Patient weight at baseline should be used for dosing calculations in patients ≤30 kg unless 
there is a ≥10% change in weight.  Dosing day weight can be used for dosing calculations 
instead of baseline weight per institutional standard.   
For patients <30kg, calculate the dose volume of durvalumab and number of vials needed for 
the subject to achieve the accurate dose according to Appendix B. 
Durvalumab will be administered at room temperature (approximately 25°C ) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
durvalumab,  the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 
minutes is considered a deviation. 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the 
priming volume of the infusion set used after the contents of the IV bag are fully administered, 
or complete the infusion according to institutional policy to ensure the full dose is 
administered and document if the line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes 
time allowances and temperatures. 
Durvalumab hold and infusion times 
Maximum time from needle puncture to 
start of administration 
4 hours at room temperature, 24 hours at 2°C to 
8°C 
Maximum time for IV bag infusion, 
including interruptions 
8 hours at room temperature 
 
In the event that either preparation time or infusion time exceeds the time limits outlined 
above, a new dose must be prepared from new vials.  Durvalumab does not contain 
preservatives, and any unused portion must be discarded. 
5.1.4 
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 Assessment. Subjects are monitored (pulse rate, blood 


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Drug Substance Durvalumab (Medi4736) 
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Date 10/08/2018 
 
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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 
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 discontinued. 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, with maximum total time at room temperature not 
exceeding 4 hours (otherwise requires new infusion preparation).   
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. 
5.1.5 
Accountability and dispensation 
Research pharmacy at each investigational site will be responsible for Durvalumab 
accountability and dispensation. The investigator’s or site’s designated investigational product 
manager is required to maintain accurate investigational product accountability records. Upon 
completion of the study, copies of investigational product accountability records will be 
returned toMedImmune.  
5.1.6 
Disposition of unused investigational study drug 
All unused investigational product will be returned to a MedImmune authorized depot or 
disposed of upon authorization by MedImmune. The sites will account for all investigational 
study drug dispensed and also for appropriate destruction.  Certificates of delivery and 
destruction must be signed. 


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Drug Substance Durvalumab (Medi4736) 
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6. 
TREATMENT PLAN 
6.1 
Subject enrollment  
Subjects with BCG refractory CIS urothelial carcinoma of the bladder as defined in inclusion 
criteria will be consented and screened.  
Subjects who have completed 6 or more doses of Durvalumab and underwent month 6/week 
26 bladder biopsy would be considered evaluable. Subjects who completed less than 6 doses 
of druvalumab will not be considered evaluable but will be followed until after the month 24 
cystoscopic evaluation and biopsy. Subjects who withdrawn from the study prior to the month 
6 cystoscopic evaluation and biopsy would be replaced to ensure a total of 34 evaluable 
subjects. 
Subjects who are incorrectly enrolled but are not yet initiated on treatment should be 
withdrawn from the study.  
 
6.2 
Dosage and Administration 
Durvalumab will be given every 4 weeks at 1500 mg IV for total of 12 months/13 doses (refer 
to Section 5.1.3 and 5.1.4 for the administration and monitoring of administration of 
durvalumab).  
 
6.3 
Durvalumab Dose Modification and Toxicity Management 
For adverse events (AEs) that are considered at least partly due to administration of 
durvalumab, the following dose adjustment guidance may be applied: 
• Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
• If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of durvalumab along with appropriate continuing 
supportive care.  If medically appropriate, dose modifications are permitted for 
durvalumab (see below). 
• All dose modifications should be documented with clear reasoning and documentation 
of the approach taken. 


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In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued. These circumstances include but not limited to grade 3 toxicity at least possibly 
related to durvalumab; and prolonged grade 2 toxicity requiring dose delays for more than 2 
weeks or requiring prolonged steroid use will discontinue durvalumab. 
 
Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (see Table 1, 2, and 3 in Appendix A).  Dose reductions 
are not permitted.  
Based on the mechanism of action of durvalumab leading to T-cell activation and 
proliferation, there is the possibility of observing immune related Adverse Events (irAEs) 
during the conduct of this study.  Potential irAEs include immune-mediated enterocolitis, 
dermatitis, hepatitis, and endocrinopathies. Subjects should be monitored for signs and 
symptoms of irAEs.  In the absence of an alternate etiology (e.g., infection or PD) signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to 
be immune-related.   
Dose modification recommendations and toxicity management guidelines for immune-
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions are 
detailed in Tables 1, 2, and 3 respectively.   
In addition, management guidelines for adverse events of special interest (AESIs) are detailed 
in Section 10.1.3. All toxicities will be graded according to NCI CTCAE V4.03.  
 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 
Restrictions during the study 
Contraception 
Females of childbearing potential who are sexually active with a nonsterilized male partner 
must use 2 methods of effective contraception from screening, and must agree to continue 
using such precautions for at least 90 days following the last infusion of durvalumab; 
cessation of birth control after this point should be discussed with a responsible physician.  
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of birth control. 
• 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 in Table 4. 
• Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see Table 4) from Day 
1 and for 90 days after receipt of the final dose of investigational product. 
Table 4. 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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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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Blood donation 
Subjects should not donate blood for at least 90 days following the last infusion of 
durvalumab. 
 
7.2 
Concomitant treatment(s) 
7.2.1 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 7.2.2. 
7.2.2 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy  
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, 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 (e.g., by local surgery or radiotherapy)>> 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the 
management of investigational product-related AEs or in subjects with contrast 
allergies is acceptable. In addition, use of inhaled and intranasal corticosteroids is 
permitted. <<A temporary period of steroids will be allowed for different indications, 
at the discretion of the principal investigator (e.g., chronic obstructive pulmonary 
disease, radiation, nausea, etc).>>    
4. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the 
first dose, during treatment with durvalumab and for 30 days post discontinuation of 
durvalumab.  Inactivated vaccines, such as the injectable influenza vaccine, are 
permitted. 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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Table 5. Prohibited and 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, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc]) 
Should be used when necessary for all patients 
8. 
STUDY PROCEDURES 
8.1 
Schedule of study procedures 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated.  
The Schedules of Assessments during the screening and treatment period is provided 
following the Protocol Synopsis (note that these are the minimum requirements and the table 
will be adjusted according to each individual study).  
8.1.1 
Screening Phase 
Subjects with BCG refractory CIS urothelial bladder cancer will be consented and then 
screened for the study. Screening procedures will be performed up to 28 days before Day 1 
Cycle 1, unless otherwise specified.  All subjects must first read, understand, and sign the 
IRB/REB/IEC-approved ICF before any study-specific screening procedures are performed.  
After signing the ICF, completing all screening procedures, and being deemed eligible for 
entry, subjects will be enrolled in the study.  Procedures that are performed prior to the 
signing of the ICF and are considered standard of care may be used as screening assessments 
if they fall within the 28-day screening window.  


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Drug Substance Durvalumab (Medi4736) 
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The following procedures will be performed during the Screening Visit: 
• Informed Consent 
• Review of eligibility criteria 
• Medical history and demographics 
• Complete physical exam  
• ECOG Performance Status 
• Vitals signs, weight and height  
• 12-lead ECG (in triplicate [2-5 minutes apart]) 
• Review of prior/concomitant medications  
• CT urogram and chest X-ray to rule out metastasis 
• Clinical laboratory tests for: 
o Hematology (see Table 6) 
o Clinical chemistry (see Table 7) 
o TSH 
o Coagulation (PT, PTT, INR) 
o Creatinine Clearance 
o Serum pregnancy test (for women of childbearing potential only) 
o Hepatitis serologies 
o Urinalysis (see Table 8) 
o Urine cytology with Urovysion FISH test 
8.1.2 
Treatment Phase  
Procedures to be conducted during the treatment phase of the study are presented in the 
Schedule of Assessments.  Screening procedures performed within 72 hours of Cycle 1 Day 1 
(C1D1) do not need to be repeated on C1D1. 
8.1.3 
End of Treatment 
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For subjects who discontinue durvalumab prior to 12 months, end of treatment is considered 
the last visit where the decision is made to discontinue treatment. All required procedures may 
be completed within ± 7 days of the end of treatment visit. <<Repeat disease assessment is not 
required if performed within 28 days prior to the end of treatment visit.>>  


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
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Assessments for subjects who have completed durvalumab treatment and achieved disease 
control, or have discontinued durvalumab due to toxicity in the absence of confirmed 
progressive disease are provided in APPENDIX C.    
Assessments for subjects who have discontinued durvalumab treatment due to confirmed PD 
are presented in APPENDIX D.  
 
8.2 
Description of study procedures 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and vital 
signs 
Findings from medical history (obtained at screening) and physical examination shall be given 
a baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-
skeletal (including spine and extremities), genital/rectal, and neurological systems and at 
screening only, height.   
ECGs are required during screening as well as at any other time point when clinically 
indicated. ECGs recorded during the screening period will be obtained in triplicate (with 2-5 
minute lag time between each). All 12-lead ECGs should be recorded while the subject is in 
the supine position for at least 5 minutes in each case.  
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on 
study days noted in the Schedule of Assessments. On durvalumab treatment days, vital signs 
will be measured within an hour prior to start of durvalumab administration, at 30 minutes 
during the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 
minutes) and 60 minutes (± 5 minutes) post-infusion.  If the infusion takes longer than 60 
minutes, then blood pressure and pulse measurements should follow the principles described 
here, or more frequently if clinically indicated.  For subsequent doses, the 1-hour observation 
period will not be required unless a subject experiences an infusion-related reaction.  


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
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8.2.2 
Clinical laboratory tests 
The following clinical laboratory tests will be performed at each study site with reference 
range for each test provided (see the Schedule of Assessments, Appendix C and Appendix D 
for the timepoints of each test): 
• Hematology (Table 6) 
• Clinical Chemistry (Table 7) 
• Coagulation parameters: Activated partial thromboplastin time and International 
normalised ratio to be assessed at baseline and as clinically indicated  
• Urine analysis (Table 8) 
• Urine cytology with Urovysion FISH test 
• Thyroid Stimulating Hormone 
o 
free T3 and free T4 only if TSH is abnormal 
• Pregnancy test (female subjects of childbearing potential only) 
o 
Urine human chorionic gonadotropin 
o 
Serum beta-human chorionic gonadotropin (at screening only) 
• Other laboratory tests 
o 
 Hepatitis B surface antigen, hepatitis C antibody 
o 
HIV antibody 
 


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Date 10/08/2018 
 
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Table 6. Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean corpuscular hemoglobin concentration 
 
 
 
 
Table7. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferaseb 
Uric acid 
a   If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect  
bilirubin 
b At baseline and as clinically indicated 
 
Table 8. Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 


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Edition Number 1.9.4 
Date 10/08/2018 
 
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a  Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red 
blood cells 
 
8.3 
Biological sampling procedures for PD-L1 testing 
To ensure comparability of data across all studies of durvalumab, the Ventana SP263 assay 
will be used for testing PD-L1 expression. Testing should be restricted to the Ventana SP263 
assay and should be performed in accordance with the package insert on the Ventana 
Benchmark platform (Ultra or XT).   
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and 
squamous cell carcinoma of the head & neck (SCCHN).  For these tumors, the Ventana SP263 
assay has a fully reproducibility data package supporting cut-off and scoring algorithm.  
Following completion of ATLANTIC and HAWK clinical trials, the assay will be associated 
with clinical utility.  In other cancer types (bladder, pancreatic, gastric, hepatocellular, triple 
negative breast, ovarian, esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, 
cholangiocarcinoma, small cell lung, melanoma and cervical HPV+ cancers), the Ventana 
SP263 assay has only limited clinical performance data.   
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.   
• The preferred bladder biopsies or TURBT sample for PD-L1 testing was less than or 
equal to 90 days old.  In cases where a sample of less than 90 days old was not 
available, patients were asked to undergo a new cystoscopic bladder biopsy and or 
TURBT.   
• 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 CIS sample with adequate tumor cell quantity is not 
clinically feasible, archival samples may be utilized provided the specimen it is not 


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older than 3 years of age.  When archival samples are used to assess PD-L1 status, the 
age of the sample / date of collection should be captured.   
• Samples submitted for PD-L1 testing should be formalin fixed and embedded in 
paraffin.   
 
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 fields of data should be collected from 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 


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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.   
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.  
• Samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) and 
embedded in the same block.  
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  
• Below is the suggested routine overnight processing schedule: 
Storage of tumor blocks for PD-L1 testing 


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Date 10/08/2018 
 
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• 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 
in order for sectioning to occur at the laboratory.  Blocks should be shipped  - 
containing enough  material to  be provided to allow a minimum of 5, and preferably 
10, sections to be cut (each 4  micron thick) to be used for PD-L1 testing.    
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 5-10 x 4 micron (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 Slides are stable under these conditions for 6 months. 
• patient samples 
• 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. 


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Date 10/08/2018 
 
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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. 
9. 
DISEASE EVALUATION AND METHODS 
The response to immunotherapy may differ from the typical responses observed with 
cytotoxic chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• Response to immunotherapy may be delayed 
• Response to immunotherapy may occur after 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, subjects with persistent 
CIS at the month 3 bladder biopsy will continue to receive Durvalumab until the month 6 
bladder biopsy documented persistent CIS or progression to the muscle invasive stage. 
Durvalumab will be discontinued and subjects will be off study if invasive bladder cancer (T1 
or above) is documented in any of the bladder biopsies. Due to the nature of CIS of bladder, 
RECIST 1.1 or irRECIST will not be applicable to response assessment. 
 
9.1.1 
Pathological response 
The absence of CIS of bladder on the mapping biopsies after pathological review would be 
considered complete response to treatment. Subjects who are withdrawn from durvalumab 
treatment for reasons other than confirmed progression to the muscle invasive stage will 
continue to have objective tumor assessments (see Appendix C).   
 
9.1.2 
Urine Cytology and UroVysion test 
Positive urine cytology and or positive UroVysion test would indicate cancer either within or 
outside bladder (upper tract or prostatic uretheral). These data will be collected at baseline, 
month 6, and 24. Only pathological response will be used to assess the primary and secondary 
objectives. 


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9.1.3 
Compare the tumor mutation burden and alterations in DNA repair genes in 
the pre and post Durvalumab urothelial bladder cancer samples 
This will be performed on the TEMPUS xT gene panel, which detects single nucleotide 
variants, indels, and copy number variant in 595 genes with tumor DNA sequencing. 
Microsatellite instability status and tumor mutation burden will be reported as well.  
10. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
10.1 
Safety Parameters 
10.1.1  Definition of adverse events 
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. 
10.1.2 
Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
Results in death 
Is immediately life-threatening 
Requires in-patient hospitalization or prolongation of existing hospitalization  
Results in persistent or significant disability,  incapacity, or substantial disruption of the 
ability to conduct normal life functions   
Is a congenital abnormality or birth defect in offspring of the subject 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of drug dependency or drug abuse. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
10.1.3 
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 durvalumab and may require close monitoring and rapid communication by 
the investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of durvalumab. 
AESIs 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. 


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These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An immune-related adverse event (irAE) is defined as an adverse 
event that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate aetiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the irAE.  
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• 
Colitis 
• 
Pneumonitis 
• 
ALT/AST increases / hepatitis / hepatotoxicity  
• 
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• 
Dermatitis 
• 
Nephritis 
• 
Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased 
serum amylase)   
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure.  
10.1.4 
Pneumonitis 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis, 
interstitial lung disease (ILD) has been reported with anti-PD-1 MAbs (Topalian et al, NEJM 
2012). Initial work-up should include high-resolution CT scan, ruling out infection, and pulse 
oximetry. Pulmonary consultation is highly recommended.  
Guidelines for the management of subjects with immune-mediated events including 
pneumonitis are outlined in Section 6.6.1. 
10.1.5 
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 


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anaphylactoid reactions against the MAb, and serum sickness. Acute allergic reactions may 
occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, 
arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, 
vomiting and unresponsiveness. 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in Section 6.6.1. 
10.1.6 
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 Table 1. 
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. 
10.1.7 
Gastrointestinal disorders 
Guidelines on management of diarrhea and colitis in patients receiving durvalumab are 
provided in Table 1. 


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10.1.8 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- 
and hypothyroidism.  Guidelines for the management of patients with immune-mediated 
endocrine events are provided in Table 1. 
10.1.9 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Table 1. 
10.1.10 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of 
patients with immune-mediated neurotoxic events are provided in Table 1. 
10.1.11 
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 
Table 1. 


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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. 
 
10.2 
Assessment of safety parameters 
10.2.1 
Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03. The 
determination of severity for all other events not listed in the CTCAE should be made by the 
investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below. 
Grade 1 (mild)  
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
 
Grade 2 (moderate)  An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm 
to the subject. 
 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the subject. 
 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with 


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an imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the subject to perform activities of daily 
living (eating, ambulation, toileting, etc). 
 
Grade 5 (fatal)  
Death (loss of life) as a result of an event. 
 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 10.1.2. A Grade 
3 AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE. 
 
10.2.2 
Assessment of relationship 
Assessment of relationship between AEs and Durvalumab will be performed by the treating 
physician/investigator at the time of each clinic visit. Such assessment will be based on 
investigators clinical judgment and the known AEs of Druvalumab. 
10.3 
Recording of adverse events and serious adverse events 
Adverse events will be recorded using a recognized medical term or diagnosis that accurately 
reflects the event and captured in OnCore. Adverse events will be assessed by the investigator 
for severity, relationship to the investigational product, possible etiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to 
AstraZeneca/MedImmune Patient Safety.  
The following variables will be collected for each AE: 
• AE (verbatim) 
• The date  when the AE started and stopped 
• Changes in NCI CTCAE grade and the maximum CTC grade attained 
• Whether the AE is serious or not 
• Investigator causality rating against durvalumab  
• Action taken with regard to durvalumab /comparator/combination agent 
• Outcome 
 


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In addition, the following variables will be collected for SAEs as applicable: 
• Date AE met criteria for serious AE 
• Date Investigator became aware of serious AE 
• AE is serious due to <<criteria>> 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 
• Description of AE 
• Causality assessment in relation to Study procedure(s) 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. Disease progression can be considered as a worsening of a patient’s 
condition attributable to the disease for which the investigational product is being studied.  It 
may be an increase in the severity of the disease under study and/or increases in the symptoms 
of the disease.  The development of new metastasis of the primary cancer under study should 
be considered as disease progression and not an AE. 
10.3.1 
Study recording period and follow-up for adverse events and serious adverse 
events 
Adverse events and serious adverse events will be recorded from time of signature of 
informed consent, throughout the treatment period and including the follow-up period (90 
days after the last dose of durvalumab) 
During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
assessments. 
The investigator is responsible for following all SAEs until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 


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Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF.  
After 90 days, only subjects with ongoing investigational product-related SAEs will continue 
to be followed for safety. 
AstraZeneca/MedImmune retains the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for 
the investigator to actively report information on new AE or SAEs occurring in former study 
subjects after the 90-day safety follow-up period for patients treated with durvalumab.  
However, if an investigator learns of any SAEs, including death, at any time after the subject 
has been permanently withdrawn from study, and he/she considers there is a reasonable 
possibility that the event is related to study treatment, the investigator should notify the study 
sponsor and AstraZeneca/MedImmune Drug Safety. 
 
10.3.2 
Reporting of serious adverse events 
Information about all serious adverse events will be collected and recorded. All SAEs will be 
reported, whether or not considered causally related to the investigational product, or to the 
study procedure(s). The reporting period for SAEs is the period immediately following the 
time that written informed consent is obtained through 90 days after the last dose of 
durvalumab or until the initiation of alternative anticancer therapy.  To ensure patient safety, 
each serious adverse event must be reported to the PI and to the sponsor expeditiously. Moffitt 
Cancer Center and all participating sites will report SAEs by completing an SAE report in 
OnCore, the electronic data capture system. The SAE must be reported by email 
(affiliate.research@moffitt.org) to the External Site Coordination (ESC) office within 2 
working days. If applicable, the site should also follow protocol guidelines for additional 
reporting to government agencies. 
The investigator and Sponsor are responsible for informing the Regulatory Authority of the 
SAE as per local requirements. 
The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs form, of any 
serious or unexpected adverse events that occur in accordance with the reporting obligations 
of 21 CFR 312.32, and will concurrently forward all such reports to AstraZeneca.  A copy of 
the MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is reported 


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to the FDA.  It is the responsibility of the sponsor to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting requirement timelines 
and to ensure that these reports are also submitted to AstraZeneca at the same time. 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
“Notification from an Investigator Sponsored Study” 
The investigator IND number assigned by the FDA 
The investigator’s name and address 
The trial name/title and AstraZeneca ISS reference number (ESR-##-#####) 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious adverse 
events.  This information should be reported on a monthly basis and under no circumstance 
less frequently than quarterly.  
10.3.3 
Reporting of deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab safety follow-up period must be reported as follows: 
Death that is clearly the result of disease progression should be documented but should not be 
reported as an SAE. 
Where death is not due (or not clearly due) to progression of the disease under study, the AE 
causing the death must be reported to as a SAE within 24 hours (see Section 10.3.2 for further 
details).  The report should contain a comment regarding the co-involvement of progression of 
disease, if appropriate, and should assign main and contributory causes of death.   
Deaths with an unknown cause should always be reported as a SAE.   


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Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented <<as events for survival analysis>>, but will not be 
reported as an SAE. 
10.3.4 
Other events requiring reporting 
10.3.5 
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 within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox 
(see Section 10.3.2 for contact information). The following information should be provided in 
the event of an Overdose (Overdose Report Form can be provided upon request):  
• Details of the Patient who was dispensed study medication (Randomization code) 
• Details of the Patient who took the overdose (demographic information, was patient a 
study participant?) 
• Details of the  drug overdose (total daily dose, route, formulation, Overdose start and 
stop dates) 
• Was the overdose accidental or intentional?  
• Was the overdose associated with an adverse event (serious or non-serious) 
• Provide an Adverse Event description (use same wording as in CRF). Provide start and 
stop dates of the event, or indicate if the event is ongoing. 
• Provide Investigator’s signature and date. 
If the overdose results in an AE, the AE must also be recorded as an AE (see Section 10.3). 
Overdose does not automatically make an AE serious, but if the consequences of the overdose 
are serious, for example death or hospitalization, the event is serious and must be recorded and 
reported as an SAE (see Section 10.1.2 and Section 10.3.2). There is currently no specific 
treatment in the event of an overdose of durvalumab.  
The investigator will use clinical judgment to treat any overdose. 
10.3.6 
Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 10.1.3.3) in a study subject, with or 
without associated clinical manifestations, is required to be reported as “hepatic function 
abnormal” within 24 hours of knowledge of the event to the sponsor and 


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AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox (see Section 
10.3.2 for contact information), unless a definitive underlying diagnosis for the abnormality 
(e.g., cholelithiasis or bile duct obstruction) that is unrelated to investigational product has 
been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to investigational product, the decision to continue dosing of the study subject will be based on 
the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
10.3.7 
Pregnancy 
10.3.8 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but 
no later than 24 hours of when he or she becomes aware of it.   
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available.   


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10.3.9 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab monotherapy.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner.  Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Institutional Review Boards (IRBs) prior to use.   
 
11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1 
Description of analysis sets 
 
11.1.1 
Safety analysis set 
Subjects who have received at least one dose of Durvalumab will be included in the Safety 
Analysis Set 
11.1.2 
Efficacy analysis set 
Subjects who have completed at least 6 treatments of every 4 week Durvalumab IV infusions 
and underwent the month 6 mapping biopsy will be included in the efficacy analysis set. 
Intention to treat analysis will be performed on all subjects who have completed at least one 
dose of Durvalumab and underwent the month 6 mapping biopsy. 
 


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11.2 
Methods of statistical analyses 
The null hypothesis that the 18% historical complete response rate at month 6 will be tested 
against a one-sided alternative of 40% or higher complete response rate with Durvalumab at 
month 6 in BCG refectory CIS of bladder.  We use a Simon's two-stage design (Simon, 1989) 
based on the optimal two-stage designs and admissible designs (Jung et al. 2004) for Phase II 
single arm clinical trials. 
 
In the first stage of this study plan, 13 patients will be accrued. If there are 3 or fewer 
responses in these 13 patients, the study will be stopped. Otherwise, 21 additional patients will 
be accrued for a total of 34. The null hypothesis will be rejected if 9 or more responses are 
observed in 34 patients. In summary 34 is the total number of subjects required, 13 is the 
number of subjects accrued during stage 1, if 3 or fewer responses are observed during stage 
1, the trial is stopped early for futility, and, if 9 or fewer responses are observed by the end of 
stage two, then no further investigation of the drug is warranted. This design yields a one-
sided type I error rate of 0.047 and power of 80% when the true response rate is 40%. 
 
The primary analysis will be performed for the (complete) response rate based on month 6 
mapping biopsy. We will use an exact probability method such as Chi-square and binomial 
tests. 
 
 
n 
n1 
r1 r2 Type 1 Error 
Power 
EN0 
Probability of early stopping Interval for w Comment 
34 13 3 9 
0.0473 
0.8031 17.1 
0.8061 
[0,0.1243] 
Optimal 
 
EN0 is the expected sample size for the trial when response rate is p0 
Interval for w is the set of values w such that the design minimizes w * 21 + (1 – w) * EN0 
 
11.2.1 
Safety Analyses 
Descriptive statistics will be applied to safety analysis 
 


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11.2.2 
Efficacy Analyses 
Descriptive statistics will be applied to Efficacy analyses/pathological response rates at month 
6 and 24.  
11.2. 3     Exploratory Analysis 
Due to the small sample size, descriptive statistics will be applied to assess putative 
associations between pathological response rates at month 6 and 24 and PD-L1 IHC positivity; 
between pathological response rates and chromosomal abnormalities observed in the 
Urovysion test. PD-L1 IHC on formalin-fixed paraffin-embedded tumor blocks will be 
performed by AstraZeneca. Urine Urovysion test is a standard of care test and will be 
performed at Moffitt Cancer Center. 
11.2.3 
Interim analyses 
Interim analysis of this study will be performed when 13 patients have been enrolled and 
completed the protocol required month 6 biopsy. If there are 3 or fewer responses in these 13 
patients, the study will be stopped. Otherwise, the study will be continued and 21 additional 
patients will be accrued for a total of 34. 
 
11.3 
Determination of sample size 
The required total number of subjects is 34. 13 is the number of subjects accrued during stage 
1. If 3 or fewer responses are observed during stage 1, the trial is stopped early for futility. 
If 9 or fewer responses of total 34 patients are observed by the end of stage two, then no 
further investigation of the drug is warranted. This design yields a one-sided type I error rate 
of 0.047 and power of 80% when the true response rate is 40% based on Simon’s optimal two-
stage design. 
12. 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 


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12.2 
Ethics and regulatory review 
Institution’s scientific review committee (SRC) conducts a formal internal peer review of all 
clinical protocols and general scientific oversight of interventional clinical research. Protocols 
are reviewed for scientific merit, adequate study design, safety, availability of targeted study 
population, and feasibility of timely completion of all proposed research projects to be 
conducted by its assigned programs at the Cancer Center.  The SRC is responsible for 
evaluating the risk/benefit assessment and corresponding data and safety monitoring plan as 
part of the scientific review and approval process.   
An IRB should approve the final study protocol, including the final version of the ICF and any 
other written information and/or materials to be provided to the subjects. The investigator will 
ensure the distribution of these documents to the applicable IRB, and to the study site staff. 
The review of this protocol by the IRB and the performance of all aspects of the study, 
including the methods used for obtaining informed consent, must also be in accordance with 
principles enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of 
Federal Regulations (CFR), Part 50 Protection of Human Subjects and Part 56 Institutional 
Review Boards. 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. Principal investigator at each site is 
responsible for providing the IRB with reports of any serious and unexpected adverse drug 
reactions from any other study conducted with Durvalumab. 
 
12.3 
Informed consent 
The Principal Investigator(s) at each center will: 
• Ensure each subject is given full and adequate oral and written information about the nature, 
purpose, possible risk and benefit of the study 
• Ensure each subject is notified that they are free to discontinue from the study at any time 
• Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study 
• Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 


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• Ensure a copy of the signed ICF is given to the subject 
• Ensure that any incentives for subjects who participate in the study as well as any provisions 
for subjects harmed as a consequence of study participation are described in the ICF that is 
approved by an IRB 
12.4 
Changes to the protocol and informed consent form 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol. The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
SRC, before implementation. 
 
12.5 
Audits and inspections 
Authorized representatives of Moffitt cancer center, a regulatory authority, or an IRB may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice, 
guidelines of the ICH, and any applicable regulatory requirements. 
13. 
STUDY MANAGEMENT 
13.1 
Training of study site personnel 
Before the first subject is entered into the study, principle investigators at each site will review 
and discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized. The principal investigator will ensure that appropriate training relevant to the study is 
given to all of these staff, and that any new information relevant to the performance of this 
study is forwarded to the staff involved. 
The principal investigator will maintain a record of all individuals involved in the study 
13.2 
Monitoring of the study 
The protocol monitoring committee (PMC) at Moffitt cancer center meets once a month.  The 
PMC reviews and evaluates safety and/or efficacy data for all physician authored clinical 
intervention trials. The PMC ensures the safety of patients and the validity and integrity of 
data. PMC reviews SAEs, deviations, Interim analysis, interim and final reports from the 
external Data Monitoring Committee (DMC) as well as audits both internally and externally. 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
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The PMC can make the following determinations, Accepted, Acceptable with Corrective 
Action and Tabled.    
13.3 
Study timetable and end of study 
We anticipate having the study open for enrollment at Moffitt in February 2017and have the 
study open at additional sites before December 2018. We plan to complete enrollment of the 
first 13 pilot subjects in 6 months. If more than 3 of the first13 subjects responded to therapy, 
the study will proceed with enrolling total of 34 subjects. We anticipate enrolling the last 
subject in December 2019 and end the study in December 2021. 
13.4 Affiliate Sites Required Documentation 
Before the study can be initiated at any site, the site will be required to provide regulatory 
documentation to the External Site Coordination (ESC) office at Moffitt Cancer Center. 
Sites must provide a copy of their informed consent to the ESC office for review and 
approval prior to submission of any documents to the site’s IRB. Any changes requested 
by the site’s IRB must be provided to the ESC staff for review and approval prior to 
resubmission to the IRB. 
The ESC office must receive the following trial specific documents either by hardcopy, fax, 
or email before a site can be activated for any trial: 
1. IRB Approval Letter that includes the protocol version and date 
2. FDA Related Forms 1572/1571/310 as appropriate 
3. Signed Protocol Title Page 
4. IRB Approved Consent Form 
5. Site Delegation of Authority Log 
6. Signed Financial Interest Disclosure Forms (principal and sub investigators) 
7. Updated Investigator/Personnel documents (CVs, licenses, GCP and HSP 
training certificates, etc.) as needed 
8. Updated Laboratory Documents (certifications, normal ranges, etc.) as 
needed  
9. Signed protocol specific Task Order 
 
A study initiation teleconference will be held prior to the start of any study related activity at 
the site. Attendance is required for:  
• The site PI and appropriate research staff 
• Moffitt PI and ESC research coordinator 
 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
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The requirements of the protocol and all associated procedures and processes will be 
reviewed and agreed upon prior to the activation of the study. The ESC utilizes the EDC 
system, OnCore. OnCore training will be scheduled, if indicated, with the appropriate staff 
from the site.  
14. 
DATA MANAGEMENT 
The Principal Investigator and the Clinical Research Coordinator assigned to the case will be 
primarily responsible for maintaining all study related documents including the clinical 
research forms.  Oncore is Moffitt’s clinical trial database of record for all CRF entries and 
will be verified with source documentation. The review of medical records within PowerChart 
will be done in a manner to assure that patient confidentiality is maintained. Regulatory 
documents and case report forms will be reviewed routinely for accuracy, completeness and 
source verification of data entry, validation of appropriate informed consent process, 
adherence to study procedures, and reporting of SAEs and protocol deviations according to 
Moffitt’s Monitoring Policies. 
14.1 Data Management and Monitoring/Auditing 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents 
and case report forms will be monitored internally according to Moffitt Cancer Center 
Monitoring Policies.  Monitoring will be performed regularly to verify data is accurate, 
complete, and verifiable from source documents; and the conduct of the trial is in compliance 
with the currently approved protocol/amendments, Good Clinical Practice (GCP), and 
applicable regulatory requirements. 
 
To obtain access to OnCore, the External Site Coordination (ESC) office Coordinator will 
supply forms required to be completed by the site staff. Once the completed forms are 
received, the site coordinator will receive DUO access, logon/password, and information on 
how to access OnCore. The ESC office will provide OnCore training to the site once initial 
access is granted and on an ongoing basis, as needed. 
 
14.2 Study governance and oversight 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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15. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
15.1 
Identity of investigational product(s) 
 
Table 1. List of investigational products for this study 
Investigational product 
Dosage form and strength 
Manufacturer 
Durvalumab 
1500 mg, solution, IV 
MedImmune 
 
 
 
 
16. 
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Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L, et al.  The PD-1/PD-L1 axis 
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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 79 of 113 
 
Chow et al. Exploring novel immune-related toxicities and endpoints with immune-checkpoint 
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Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
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Coleman RL, Monk BJ, Sood AK, et al: Latest research and treatment of advanced-stage 
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Dinney CP, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder 
carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin. Urol 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 
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European Medicines Agency’s “Guideline on the evaluation of anti-cancer medicinal products 
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Fagotti A, Ferrandina G, Fanfani F, et al: A laparoscopy-based score to predict surgical 
outcome in patients with advanced ovarian carcinoma: a pilot study. Ann Surg Oncol 2006; 
13:1156-61. 
 
Fellman, B. M. Stata command for calculating adverse event and efficacy stopping boundaries 
for phase II single-arm trials. Stata Journal. 2014; 14(2):407-417. 
Food and Drug Administration Guidance for Industry (issued July 2009) ‘Drug-induced liver 
injury: Premarketing clinical evaluation’.  Available from URL: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf.  Accessed 10 December 2013. 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Nat Acad Sci U S A. 2007;104(9):3360-5. 
 
Hamid et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N 
Engl J Med. 2013;369(2):134-44 
 
Inman BA, Sebo TJ, Frigola X, et al: PD-L1 (B7-H1) expression by urothelial carcinoma of 
the bladder and BCG-induced granulomata: associations with localized stage progression. 
Cancer. 2007;109(8):1499-505 
 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 80 of 113 
 
Jarow JP, Lerner SP, Kluetz PG, et al: Clinical trial design for the development of new 
therapies for nonmuscle-invasive bladder cancer: report of a Food and Drug Administration 
and American Urological Association public workshop. Urology. 2014; 83(2):262-4 
 
Jung SH, Lee TY, Kim KM, George S (2004). Admissible two-stage designs for phase II 
cancer clinical trials, Statistics in Medicine 23: 561-569.  
 
Kaehler et al. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: 
identification of clinical and biological response patterns, immune-related adverse events, and 
their management. Semin Oncol. 2010 Oct;37(5):485-98 
 
Kandalaft LE, Motz GT, Duraiswamy J, et al: Tumor immune surveillance and ovarian 
cancer: lessons on immune mediated tumor rejection or tolerance. Cancer Metastasis Rev 
2011; 30:141-51. 
 
Katsumata N, Yasuda M, Takahashi F, et al: Dose-dense paclitaxel once a week in 
combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-
label, randomised controlled trial. Lancet 2009; 374:1331-8. 
 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol. 2008;26:677-704. 
 
Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and 
clinicopathologic findings. Invest New Drugs. 2013;31:1071. 
 
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al: Survivin 
and B7-H1 are collaborative predictors of survival and represent potential therapeutic targets 
for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1749-56. 
 
Kryczek I, Wei S, Zhu G, et al: Relationship between B7-H4, regulatory T cells, and patient 
outcome in human ovarian carcinoma. Cancer Res 2007; 67:8900-5. 
 
Lam JS, Benson MC, O'Donnell MA, et al: Bacillus Calmete-Guérin plus interferon-alpha2B 
intravesical therapy maintains an extended treatment plan for superficial bladder cancer with 
minimal toxicity. Urol Oncol. 2003; 21(5):354-60 
 
Lenz.  Management and preparedness for infusion and hypersensitivity reactions.  Oncologist. 
2007;12(5):601-9. 
 
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance 
and regulation of the costimulatory molecule B7-H1 in pancreatic adenocarcinoma. Cancer 
Lett. 2008;268(1):98-109. 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 81 of 113 
 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer 
may contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol. 2011 Sep;28(3):682-8. 
 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS.  Developing 
a common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements.  Clin Cancer Res.  2013 Jul; 19(14):3936-3943. 
 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic adenocarcinoma. Clin Cancer Res. 2007 Apr 1;13(7):2151-7. 
 
Park J, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 
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Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. The 
New England journal of medicine 2011; 365:2484-96. 
 
Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical 
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Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 82 of 113 
 
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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 83 of 113 
 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and  
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination 
Therapy With Tremelimumab or Tremelimumab Monotherapy) 1 November 
2017 Version 
General Considerations 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study 
regimen will be made to manage potential immune-related 
AEs based on severity of treatment-emergent toxicities graded 
per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of 
study drug/study regimen based on CTC grade/severity (table 
below), permanently discontinue study drug/study regimen for 
the following conditions: 
• 
Inability to reduce corticosteroid to a dose of 
≤10 mg of prednisone per day (or equivalent) within 
12 weeks after last dose of study drug/study regimen 
• 
Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of 
dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or 
Grade 4. 
Study drug/study regimen can be resumed once 
event stabilizes to Grade ≤1 after completion of 
steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per 
Investigator or treating physician’s clinical 
judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or 
equivalent. 
Grade 3 
Depending on the individual toxicity, study 
drug/study regimen may be permanently 
It is recommended that management of immune-mediated 
adverse events (imAEs) follows the guidelines presented in 
this table: 
− 
It is possible that events with an inflammatory or 
immune mediated mechanism could occur in 
nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events 
(and/or laboratory indicators of such events) are 
noted in these guidelines or not, patients should 
be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, 
concomitant medications, and infections) to a 
possible immune-mediated event. In the absence 
of a clear alternative etiology, all such events 
should be managed as if they were immune 
related. General recommendations follow. 
− 
Symptomatic and topical therapy should be 
considered for low-grade (Grade 1 or 2, unless 
otherwise specified) events.  
− 
For persistent (>3 to 5 days) low-grade (Grade 2) 
or severe (Grade ≥3) events, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity 
and/or mortality – e.g., myo-carditis, or other 
similar events even if they are not currently noted 
in the guidelines – should progress rapidly to high 
dose IV corticosteroids (methylprednisolone at 2 
to 4 mg/kg/day) even if the event is Grade 2, and 
if clinical suspicion is high and/or there has been 
clinical confirmation. Consider, as necessary, 
discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during 
corticosteroid tapering (28 days of taper), 
increase the corticosteroid dose (prednisone dose 
[e.g., up to 2 to 4 mg/kg/day PO or IV 
equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at 
a slower rate (>28 days of taper). 
− 
More potent immunosuppressives such as TNF 
inhibitors (e.g., infliximab) (also refer to the 
individual sections of the imAEs for specific type 
of immunosuppressive) should be considered for 
events not responding to systemic steroids. 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
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Date 10/08/2018 
 
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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and  
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination 
Therapy With Tremelimumab or Tremelimumab Monotherapy) 1 November 
2017 Version 
General Considerations 
Dose Modifications 
Toxicity Management 
discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study 
regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, 
hold study drug/study regimen, and if complete work up 
shows no evidence of pancreatitis, study drug/study regimen 
may be continued or resumed. 
Note: Study drug/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other similar 
events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should 
be permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality – e.g., myocarditis, 
or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 
upon treatment with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation 
of study drug for Grade 4 events (i.e., hyperthyroidism, 
hypothyroidism, Type 1 diabetes mellitus).  
 
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/study regimen is 
not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be 
based upon a benefit-risk analysis for that patient. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE 
immune-mediated adverse event; IV intravenous; NCI National Cancer Institute; PO By mouth. 
 
Pediatric Considerations 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study 
drug/study regimen based on CTC grade/severity is the 
same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study 
regimen if unable to reduce corticosteroid ≤ a dose 
− 
All recommendations for specialist consultation 
should occur with a pediatric specialist in the 
specialty recommended. 
− 
The recommendations for dosing of steroids (i.e., 
mg/kg/day) and for IV IG and plasmapheresis that are 
provided for adult patients should also be used for 
pediatric patients. 


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Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
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Pediatric Considerations 
Dose Modifications 
Toxicity Management 
equivalent to that required for corticosteroid replacement 
therapy within 12 weeks after last dose of study 
drug/study regimen 
− 
The infliximab 5 mg/kg IV dose recommended for 
adults is the same as recommended for pediatric 
patients ≥ 6 years old.  For dosing in children younger 
than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, 
consult with a pediatric specialist. 
− 
With long-term steroid and other immunosuppressive 
use, consider need for PJP prophylaxis, 
gastrointestinal protection, and glucose monitoring. 
 
 


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Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 86 of 113 
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of pneumonitis or ILD 
(new onset or worsening shortness of 
breath or cough). Patients should be 
evaluated with imaging and 
pulmonary function tests, including 
other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical 
evaluation, monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), laboratory 
work-up, and high- resolution CT 
scan. 
Grade 1 
(asymptomatic, 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated) 
No dose modifications 
required. However, 
consider holding study 
drug/study regimen dose 
as clinically appropriate 
and during diagnostic 
work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms, pulse 
oximetry (resting and exertion), and 
laboratory work-up and then as 
clinically indicated. 
− 
Consider Pulmonary and Infectious 
disease 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/study 
regimen will be 
based upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper. 
For Grade 2 (mild to moderate new 
symptoms): 
− 
Monitor symptoms daily and 
consider hospitalization. 
− 
Promptly start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 
days, additional workup should be 
considered and prompt treatment 
with IV methylprednisolone 2 to 
4 mg/kg/day started 
− 
If still no improvement within 3 to 5 
days despite IV methylprednisolone 
at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It 
is important to rule out sepsis and 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 87 of 113 
 
refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation])a 
− 
Consider pulmonary and infectious 
disease consult. 
− 
Consider, as necessary, discussing 
with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; 
limiting self-care 
ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated [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 study 
physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 
days, additional workup should be 
considered and prompt treatment 
with additional immunosuppressive 
therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 
weeks’ dose) started. Caution: rule 
out sepsis and refer to infliximab 
label for general guidance before 
using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and, in 
particular, anti-PJP treatment (refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be 
related to diarrhea/enterocolitis 
(abdominal pain, cramping, or 
changes in bowel habits such as 
increased frequency over baseline or 
blood in stool) or related to bowel 
perforation (such as sepsis, 
peritoneal signs, and ileus). 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 88 of 113 
 
− 
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. 
− 
Use analgesics carefully; they can 
mask symptoms of perforation and 
peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 
over baseline per 
day) 
(Colitis: 
asymptomatic; 
clinical or 
diagnostic 
observations 
only) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening 
symptoms. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide. Use probiotics 
as per treating physician’s clinical 
judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 
6 over baseline 
per day) (Colitis: 
abdominal pain; 
mucus or blood 
in stool) 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1, then 
study drug/study 
regimen can be 
resumed after 
completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, GI consult should be 
obtained for consideration of further 
workup, such as imaging and/or 
colonoscopy, to confirm colitis and 
rule out perforation, and prompt 
treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
started. 
− 
If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg IV 
methylprednisolone, promptly start 
immunosuppressives such as 
infliximab at 5 mg/kg once every 2 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 89 of 113 
 
weeksa. Caution: it is important to 
rule out bowel perforation and refer 
to infliximab label for general 
guidance before using infliximab. 
− 
Consider, as necessary, discussing 
with study physician if no resolution 
to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3 
diarrhea: stool 
frequency of ≥7 
over baseline per 
day; 
Grade 4 
diarrhea: life 
threatening 
consequences) 
(Grade 3 colitis: 
severe 
abdominal pain, 
change in bowel 
habits, medi-cal 
intervention 
indi-cated, 
peritoneal signs; 
Grade 4 colitis: 
life-threatening 
consequences, 
urgent 
intervention 
indicated) 
 
Grade 3 
Permanently discontinue 
study drug/study regimen 
for Grade 3 if toxicity 
does not improve to 
Grade ≤1 within 14 days; 
study drug/study regimen 
can be resumed after 
completion of steroid 
taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day 
or equivalent. 
− 
Monitor stool frequency and volume 
and maintain hydration. 
− 
Urgent GI consult and imaging 
and/or colonoscopy as appropriate. 
− 
If still no improvement within 3 to 5 
days of IV methylprednisolone 2 to 4 
mg/kg/day or equivalent, promptly 
start further immunosuppressives 
(e.g., infliximab at 5 mg/kg once 
every 2 weeks). Caution: Ensure GI 
consult to rule out bowel perforation 
and refer to infliximab label for 
general guidance before using 
infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Hepatitis  
(elevated LFTs) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function 
test: AST, ALT, ALP, and TB. 
− 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 90 of 113 
 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
medications). 
Grade 1 
(AST or ALT 
>ULN and 
≤3.0×ULN 
and/or TB > 
ULN and  
≤1.5×ULN) 
• 
No dose 
modifications. 
• 
If it worsens, then 
treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per 
protocol. 
Grade 2 
(AST or  
ALT >3.0×ULN 
and ≤5.0×ULN 
and/or  
TB >1.5×ULN 
and  ≤3.0×ULN) 
• 
Hold study 
drug/study regimen 
dose until Grade 2 
resolution to Grade 
≤1. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, resume 
study drug/study 
regimen after 
completion of steroid 
taper. 
For Grade 2: 
− 
Regular and frequent checking of 
LFTs (e.g., every 1 to 2 days) until 
elevations of these are improving or 
resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 
days, consider, as necessary, 
discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 
days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, 
consider additional work up and start 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day. 
− 
If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, promptly start 
immunosuppressives (i.e., 
mycophenolate mofetil).a Discuss 
with study physician if 
mycophenolate mofetil is not 
available. Infliximab should NOT 
be used. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: AST 
or  
ALT >5.0×ULN 
and ≤20.0×ULN 
and/or  
For Grade 3: 
For elevations in 
transaminases ≤8 × ULN, 
or elevations in bilirubin 
≤5 × ULN: 
• Hold study 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 
days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 91 of 113 
 
TB >3.0×ULN 
and  
≤10.0×ULN) 
 
(Grade 4: AST 
or  
ALT >20×ULN 
and/or  
TB >10×ULN) 
drug/study regimen 
dose until resolution 
to Grade ≤1 or 
baseline 
• Resume study 
drug/study regimen if 
elevations downgrade 
to Grade ≤1 or 
baseline within 
14 days and after 
completion of steroid 
taper. 
• Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to Grade 
≤1 or baseline within 
14 days 
For elevations in 
transaminases >8 × ULN 
or elevations in bilirubin 
>5 × ULN, discontinue 
study drug/study regimen. 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria (AST and/or 
ALT >3 × ULN + 
bilirubin >2 × ULN 
without initial findings of 
cholestasis (i.e., elevated 
alkaline P04) and in the 
absence of any alternative 
cause.b 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
 
promptly start treatment with 
immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss 
with study physician if 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform hepatology consult, 
abdominal workup, and imaging as 
appropriate. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis  
(elevated LFTs) 
Any Grade 
 
General Guidance 
 
For Any Grade: 
− 
Monitor and evaluate liver function 
test: AST, ALT, ALP, and TB. 
− 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 92 of 113 
 
Infliximab should not be 
used for management of 
immune-related hepatitis.  
See instructions at  
bottom of shaded area  
if transaminase rise is  
not isolated but (at any 
time) occurs in setting  
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
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 
 
Grade 1 
(Isolated AST or 
ALT >ULN and 
≤5.0×ULN, 
whether normal 
or elevated at 
baseline)  
• 
No dose 
modifications. 
• 
If ALT/AST 
elevations represents 
significant worsening 
based on investigator 
assessment, then treat 
as Grade 2 event. 
For all grades, see 
instructions at bottom of 
shaded area if 
transaminase rise is not 
isolated but (at any time) 
occurs in setting of either 
increasing bilirubin or 
signs of DILI/liver 
decompensation 
 
 
Grade 2 
(Isolated AST or 
ALT >5.0×ULN 
and ≤8.0×ULN, 
if normal at 
• 
Hold study 
drug/study regimen 
dose until Grade 2 
resolution to Grade 
≤1 or baseline. 
For Grade 2: 
− 
Regular and frequent checking of 
LFTs (e.g., every 1 to 3 days) until 
elevations of these are improving or 
resolved. 
− 
Recommend consult hepatologist; 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients  


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 93 of 113 
 
baseline) 
 
(Isolated AST or 
ALT 
>2.0×baseline 
and ≤12.5×ULN, 
if elevated 
>ULN at 
baseline) 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
If toxicity improves to 
Grade ≤1 or baseline, 
resume study drug/study 
regimen after completion 
of steroid taper. 
consider abdominal ultrasound, 
including Doppler assessment of 
liver perfusion. 
− 
Consider, as necessary, discussing 
with study physician. 
− 
If event is persistent (>3 to 5 days) or 
worsens, and investigator suspects 
toxicity to be immune-mediated AE, 
recommend to start prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 
days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, 
consider additional workup and 
treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day. 
− 
If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, consider 
additional abdominal workup 
(including liver biopsy) and imaging 
(i.e., liver ultrasound), and consider 
starting immunosuppressives (i.e., 
mycophenolate mofetil).a Discuss 
with study physician if 
mycophenolate mofetil is not 
available. Infliximab should NOT 
be used. 
 
Grade 3 
(Isolated AST or 
ALT >8.0×ULN 
and ≤20.0×ULN, 
if normal at 
baseline) 
 
(Isolated AST or 
ALT 
>12.5×ULN and 
≤20.0×ULN, if  
elevated >ULN 
at baseline) 
• Hold study 
drug/study regimen 
dose until resolution 
to Grade ≤1 or 
baseline 
• Resume study 
drug/study regimen if 
elevations downgrade 
to Grade ≤1 or 
baseline within 
14 days and after 
completion of steroid 
taper. 
• Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to Grade 
≤1 or baseline within 
14 days 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
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 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 94 of 113 
 
law criteria, in the 
absence of any alternative 
cause.b 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
Grade 4 
(Isolated AST or 
ALT >20×ULN,  
whether normal 
or elevated at 
baseline) 
Permanently discontinue 
study drug/study regimen. 
For Grade 4: 
Same as above  
(except would recommend obtaining liver 
biopsy early) 
 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin 
(≥1.5×ULN, if normal at baseline; or 2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (e.g., 
fever, elevated INR): 
- 
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that 
may be related to changes in renal 
function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, 
decreased creatinine clearance, 
electrolyte imbalance, decrease in 
urine output, or proteinuria). 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression or 
infections). 
− 
Steroids should be considered in the 
absence of clear alternative etiology 
even for low-grade events (Grade 2), 
in order to prevent potential 
progression to higher grade event. 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 95 of 113 
 
(Serum 
creatinine > 1 to 
1.5 × baseline; > 
ULN to 1.5 × 
ULN) 
− 
Monitor serum creatinine weekly and 
any accompanying symptoms. 
• 
If creatinine returns to 
baseline, resume its regular 
monitoring per study 
protocol. 
• 
If creatinine worsens, 
depending on the severity, 
treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
Grade 2 
(serum 
creatinine >1.5 
to 3.0 × baseline; 
>1.5 to 3.0 × 
ULN) 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 or baseline.  
• 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, then resume 
study drug/study 
regimen after 
completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
− 
Carefully monitor serum creatinine 
every 2 to 3 days and as clinically 
warranted. 
− 
Consult nephrologist and consider 
renal biopsy if clinically indicated. 
− 
If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should 
be considered and prompt treatment 
with IV methylprednisolone at 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).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 to 
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 to 
5 days or worsens despite prednisone 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 96 of 113 
 
Grade 4: serum 
creatinine >6.0 × 
ULN) 
at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should 
be considered and prompt treatment 
with IV methylprednisolone 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI 
CTCAE v 4.03 
for definition of 
severity/grade 
depending on 
type of skin 
rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of 
dermatitis (rash and pruritus). 
− 
IF THERE IS ANY BULLOUS 
FORMATION, THE STUDY 
PHYSICIAN SHOULD BE 
CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea 
cream). 
Grade 2 
For persistent (>1 to 2 
weeks) Grade 2 events, 
hold scheduled study 
drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, 
then treat as 
Grade 3. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume drug/study 
regimen after 
completion of 
steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea 
cream). 
− 
Consider moderate-strength topical 
steroid. 
− 
If no improvement of rash/skin 
lesions occurs within 3 to 5 days or is 
worsening despite symptomatic 
treatment and/or use of moderate 
strength topical steroid, consider, as 
necessary, discussing with study 
physician and promptly start 
systemic steroids such as prednisone 
1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
Consider skin biopsy if the event is 
persistent for >1 to 2 weeks or 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 97 of 113 
 
recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 or baseline. 
If temporarily holding the 
study drug/study regimen 
does not provide 
improvement of the Grade 
3 skin rash to Grade ≤1 or 
baseline within 30 days, 
then permanently 
discontinue study 
drug/study regimen. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of 
Nines]. 
− 
Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
− 
Consider, as necessary, discussing 
with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
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 v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an 
endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Monitor patients for signs and 
symptoms of endocrinopathies. Non-
specific symptoms include headache, 
fatigue, behavior changes, changed 
mental status, vertigo, abdominal 
pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, 
and weakness. 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression 
including brain metastases, or 
infections). 
− 
Depending on the suspected 
endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, 
free T3 and free T4 and other 
relevant endocrine and related labs 
(e.g., blood glucose and ketone 
levels, HgA1c). 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 98 of 113 
 
− 
For modest asymptomatic elevations 
in serum amylase and lipase, 
corticosteroid treatment is not 
indicated as long as there are no 
other signs or symptoms of 
pancreatic inflammation. 
− 
If a patient experiences an AE that is 
thought to be possibly of 
autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or 
diabetes insipidus), the investigator 
should send a blood sample for 
appropriate autoimmune antibody 
testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with 
asymptomatic TSH elevation): 
− 
Monitor patient with appropriate 
endocrine function tests. 
− 
For suspected 
hypophysitis/hypopituitarism, 
consider consultation of an 
endocrinologist to guide assessment 
of early-morning ACTH, cortisol, 
TSH and free T4; also consider 
gonadotropins, sex hormones, and 
prolactin levels, as well as 
cosyntropin stimulation test (though 
it may not be useful in diagnosing 
early secondary adrenal 
insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × 
ULN, or consistently out of range in 
2 subsequent measurements, include 
free T4 at subsequent cycles as 
clinically indicated and consider 
consultation of an endocrinologist. 
Grade 2 
For Grade 2 
endocrinopathy other than 
hypothyroidism and Type 
1 diabetes mellitus, hold 
study drug/study regimen 
dose until patient is 
clinically stable. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
Study drug/study regimen 
can be resumed once 
event stabilizes and after 
For Grade 2 (including those with 
symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide 
evaluation of endocrine function and, 
as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
− 
For all patients with abnormal 
endocrine work up, except those with 
isolated hypothyroidism or Type 1 
DM, and as guided by an  
endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 
2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation 
of treatment with relevant hormone 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 99 of 113 
 
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. 
replacement (e.g., hydrocortisone, 
sex hormones). 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
(DM) may be treated with 
appropriate diabetic therapy, without 
study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Once patients on steroids are 
improving, gradually taper  
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines 
for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
− 
For patients with normal endocrine 
workup (laboratory assessment or 
MRI scans), repeat laboratory 
assessments/MRI as clinically 
indicated. 
Grade 3 or 4 
For Grade 3 or 4 
endocrinopathy other than 
hypothyroidism and Type 
1 diabetes mellitus, hold 
study drug/study regimen 
dose until endocrinopathy 
symptom(s) are 
controlled.  
Study drug/study regimen 
can be resumed once 
event stabilizes and after 
completion of steroid 
taper. 
Patients with 
endocrinopathies who 
may require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide 
evaluation of endocrine function and, 
as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
Hospitalization recommended. 
− 
For all patients with abnormal 
endocrine work up, except those with 
isolated hypothyroidism or Type 1 
DM, and as guided by an  
endocrinologist, promptly initiate 
empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., 
hydrocortisone, sex hormones). 
− 
For adrenal crisis, severe 
dehydration, hypotension, or shock, 
immediately initiate IV 
corticosteroids with 
mineralocorticoid activity. 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 100 of 113 
 
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. 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
may be treated with appropriate 
diabetic therapy, without study 
drug/study regimen interruption, and 
without corticosteroids. 
− 
Once patients on steroids are 
improving, gradually taper 
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines 
for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 
metabolic syndromes, or 
medications). 
− 
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness). 
− 
Consider appropriate diagnostic 
testing (e.g., electromyogram and 
nerve conduction investigations). 
− 
Perform symptomatic treatment with 
neurological consult as appropriate. 
− 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations 
above. 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to Grade 
≤1. 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to 
For Grade 2: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin or 
duloxetine). 
− 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
− 
If no improvement within 3 to 5 days 
despite 1 to 2 mg/kg/day prednisone 
PO or IV equivalent, consider 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 101 of 113 
 
Grade ≤1. 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
Study drug/study regimen 
can be resumed once 
event improves to Grade 
≤1 and after completion 
of steroid taper. 
additional workup and promptly treat 
with additional immunosuppressive 
therapy (e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 
− 
If no improvement within 3 to 5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(e.g., IV IG). 
− 
Once stable, gradually taper steroids 
over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-
mediated peripheral neuromotor 
syndromes is important, since certain 
patients may unpredictably 
experience acute decompensations 
that can result in substantial 
morbidity or in the worst case, death. 
Special care should be taken for 
certain sentinel symptoms that may 
predict 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 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 102 of 113 
 
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. 
− 
It is important to consider that the 
use of steroids as the primary 
treatment of Guillain-Barre is not 
typically considered effective. 
Patients requiring treatment should 
be started with IV IG and followed 
by plasmapheresis if not responsive 
to IV IG. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as 
described above. 
− 
Obtain a neurology consult. 
Grade 2 
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 study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as 
described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin or 
duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to treat 
myasthenia gravis. It is 
important to consider that 
steroid therapy (especially 
with high doses) may result 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 103 of 113 
 
in transient worsening of 
myasthenia and should 
typically be administered 
in a monitored setting 
under supervision of a 
consulting neurologist. 
o 
Patients unable to tolerate 
steroids may be candidates 
for treatment with 
plasmapheresis or IV IG. 
Such decisions are best 
made in consultation with a 
neurologist, taking into 
account the unique needs 
of each patient. 
o 
If myasthenia gravis-like 
neurotoxicity is present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. Such 
therapy, if successful, can 
also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider 
here that the use of steroids 
as the primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be started 
with IV IG and followed 
by plasmapheresis if not 
responsive to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency or 
autonomic instability. 
 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
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. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 104 of 113 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
o 
Patients unable to tolerate 
steroids may be candidates 
for treatment with 
plasmapheresis or IV IG. 
o 
If myasthenia gravis-like 
neurotoxicity present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. Such 
therapy, if successful, can 
also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider 
here that the use of steroids 
as the primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be started 
with IV IG and followed 
by plasmapheresis if not 
responsive to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug 
permanently if biopsy-
proven immune-mediated 
myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-
mediated myocarditis is important, 
particularly in patients with baseline 
cardiopulmonary disease and 
reduced cardiac function.  
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Monitor patients for signs and 
symptoms of myocarditis (new onset 
or worsening chest pain, arrhythmia, 
shortness of breath, peripheral 
edema). As some symptoms can 
overlap with lung toxicities, 
simultaneously evaluate for and rule 
out pulmonary toxicity as well as 
other causes (e.g., pulmonary 
embolism, congestive heart failure, 
malignant pericardial effusion). A 
Cardiology consultation should be 
obtained early, with prompt 
assessment of whether and when to 
complete a cardiac biopsy, including 
any other diagnostic procedures. 
− 
Initial work-up should include 
clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram 
(ECHO), monitoring of oxygenation 
via pulse oximetry (resting and 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 105 of 113 
 
exertion), and additional laboratory 
work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO 
to assess wall motion abnormalities 
when needed. 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, 
other medications, or infections) 
 
Grade 1 
(asymptomatic 
with laboratory 
(e.g., BNP) or 
cardiac imaging 
abnormalities) 
No dose modifications 
required unless clinical 
suspicion is high, in 
which case hold study 
drug/study regimen dose 
during diagnostic work-
up for other etiologies. If 
study drug/study regimen 
is held, resume after 
complete resolution to 
Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms,  BNP, 
cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and 
laboratory work-up as clinically 
indicated. 
- 
Consider using steroids if clinical 
suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: 
Symptoms with 
mild to moderate 
activity or 
exertion) 
 
 (Grade 3: 
Severe with 
symptoms at rest 
or with minimal 
activity or 
exertion; 
intervention 
indicated) 
 
(Grade 4: Life-
threatening 
consequences; 
urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
- If Grade 2 -- Hold 
study drug/study 
regimen dose until 
resolution to Grade 0. 
If toxicity rapidly 
improves to Grade 0, 
then the decision to 
reinitiate study 
drug/study regimen 
will be based upon 
treating physician’s 
clinical judgment and 
after completion of 
steroid taper. If 
toxicity does not 
rapidly improve, 
permanently. 
discontinue study 
drug/study regimen. 
If Grade 3-4, permanently 
discontinue study 
drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
or equivalent after Cardiology 
consultation has determined whether 
and when to complete diagnostic 
procedures including a cardiac 
biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days 
despite IV methylprednisolone at 2 
to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It 
is important to rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 106 of 113 
 
mechanical 
hemodynamic 
support)) 
 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of poly/myositis. 
Typically, muscle weakness/pain 
occurs in proximal muscles including 
upper arms, thighs, shoulders, hips, 
neck and back, but rarely affects the 
extremities including hands and 
fingers; also difficulty breathing 
and/or trouble swallowing can occur 
and progress rapidly. Increased 
general feelings of tiredness and 
fatigue may occur, and there can be 
new-onset falling, difficulty getting 
up from a fall, and trouble climbing 
stairs, standing up from a seated 
position, and/or reaching up. 
− 
If poly/myositis is suspected, a 
Neurology consultation should be 
obtained early, with prompt guidance 
on diagnostic procedures. 
Myocarditis may co-occur with 
poly/myositis; refer to guidance 
under Myocarditis. Given breathing 
complications, refer to guidance 
under Pneumonitis/ILD.  
Given possibility of an existent (but 
previously unknown) autoimmune 
disorder, consider Rheumatology 
consultation. 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Initial work-up should include 
clinical evaluation, creatine kinase, 
aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-
reactive protein level, urine 
myoglobin, and additional laboratory 
work-up as indicated, including a 
number of possible 
rheumatological/antibody tests (i.e., 
consider whether a rheumatologist 
consultation is indicated and could 
guide need for rheumatoid factor, 
antinuclear antibody, anti-smooth 
muscle, antisynthetase [such as anti-
Jo-1], and/or signal-recognition 
particle antibodies). Confirmatory 
testing may include 
electromyography, nerve conduction 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 107 of 113 
 
studies, MRI of the muscles, and/or a 
muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia 
or dysphonia. 
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms and 
initiate evaluation as clinically 
indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing 
with the study physician. 
 
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 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 108 of 113 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT 
Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; 
CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of 
normal; MRI  Magnetic resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer 
Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  By mouth; 
T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating 
hormone; ULN Upper limit of normal. 
 
 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
Grade 3 or 4 
(pain associated 
with severe 
weakness; 
limiting self-care 
ADLs) 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency. 
 
For Grade 4: 
- Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Monitor symptoms closely; 
recommend hospitalization. 
− 
Obtain Neurology consult, and 
complete full evaluation. 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with 
receiving input from Neurology 
consultant. 
− 
If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no improvement 
within 3 to 5 days, consider start of 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It 
is important to rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 
− 
Consider whether patient may 
require IV IG, plasmapheresis. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 109 of 113 
 
Infusion-Related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the 
discretion of investigator. 
− 
Monitor patients for signs and symptoms of 
infusion-related reactions (e.g., fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, or skin rashes) 
and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event. 
 
For Grade 2: 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution of 
the event. 
Subsequent infusions may be given at 
50% of the initial infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be 
administered per institutional standard at the 
discretion of the investigator. 
− 
Consider premedication per institutional 
standard prior to subsequent doses. 
− 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per 
institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer 
Institute. 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 110 of 113 
 
Non–Immune-Mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study 
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 
14 days, resume study drug/study regimen 
administration. Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 
2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 111 of 113 
 
APPENDIX B: DURVALUMAB DOSE CALCULATIONS  
Durvalumab Dosing 
The durvalumab dosing should be done depending on subject weight (if subject is < 30kg) at 
20 mg/kg: 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration  
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 
mL). Dose adjustments for each cycle only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
Example:  
1. Cohort dose: 10 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 112 of 113 
 
APPENDIX C 
Schedule of study procedures: follow-up for subjects who have discontinued 
durvalumab due to toxicity in the absence of confirmed progression of disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
30 
2 
3 
5 
7 
9 
12 
Physical examinationa 
X 
 
 
 
 
 
 
Vital signs (temperature, respiratory rate, 
blood pressure, pulse) 
X 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
<<World Health Organisation>> 
<<ECOG>> performance statusb 
X 
X 
X 
 
 
 
 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with 
subjects who refuse to return for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
Urine hCG or serum βhCG 
X 
 
 
 
 
 
 
Hematology 
X 
X 
X 
 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
 
Thyroid function tests (TSH, and fT3 and 
fT4)c 
X 
 
 
 
 
 
 
Tumour assessment (CT or MRI)  
At the discretion of treating physician, which is not 
indicated until the localized bladder cancer 
progressed to the muscle invasive stage (T2 or 
above)    X 
 
 
 
 
 
 
a  
Full physical exam 
b 
PS to be collected if available at the 2 monthly calls to obtain subsequent anti-cancer therapy and survival status 
c 
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. 


Clinical Study Protocol 
Drug Substance Durvalumab (Medi4736) 
Study Number MCC 18788/MCC18788/ESR-15-11326 
Edition Number 1.9.4 
Date 10/08/2018 
 
Page 113 of 113 
 
APPENDIX D  
Schedule of study procedures: follow-up for subjects who have 
discontinued durvalumab treatment due to confirmed progression of 
disease at the investigator discretion 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
30 
2 
3 
5 
7 
9 
12 
Physical examinationa 
X 
 
 
 
 
 
 
Vital signs (temperature, respiratory rate, 
blood pressure, pulse) 
X 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
<<World Health Organisation>> 
<<ECOG>> performance statusb 
X 
X 
X 
 
 
 
 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with 
subjects who refuse to return for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
Urine hCG or serum βhCG 
X 
 
 
 
 
 
 
Hematology 
X 
X 
X 
 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
 
Thyroid function tests (TSH, and fT3 and 
fT4)c 
X 
 
 
 
 
 
 
Tumour assessment (CT or MRI)  
At the discretion of treating physician, which is not 
indicated until the localized bladder cancer 
progressed to the muscle invasive stage (T2 or 
above)   X 
 
 
 
 
 
 
a   
Full physical exam 
b 
PS to be collected if available at the 2 monthly calls to obtain subsequent anti-cancer therapy and survival status 
c 
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.