Phase 2 Open Label Study of Durvalumab With Neoadjuvant Chemotherapy in Variant Histology Bladder Cancer
Phase: PHASE2
Conditions: Bladder Adenocarcinoma, Bladder Mixed Adenocarcinoma, Bladder Squamous Cell Carcinoma, Bladder Urothelial Carcinoma, Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant, Infiltrating Bladder Urothelial Carcinoma With Giant Cells, Infiltrating Bladder Urothelial Carcinoma With Glandular Differentiation, Infiltrating Bladder Urothelial Carcinoma With Trophoblastic Differentiation, Infiltrating Bladder Urothelial Carcinoma, Clear Cell Variant, Infiltrating Bladder Urothelial Carcinoma, Micropapillary Variant, Infiltrating Bladder Urothelial Carcinoma, Nested Variant, Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant
Sponsor: Stanford University

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Phase 2 Open Label Study of Durvalumab with Neoadjuvant 
Chemotherapy in Variant Histology Bladder Cancer  
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
Protocol Director: 
Sandy Srinivas, MD 
875 Blake Wilbur Dr, Stanford, CA 94305 
Telephone: 650-725-2078 
Fax: 
 
e-mail:  sandysri@stanford.edu 
Sub-Investigators: 
Alice Fan, MD 
875 Blake Wilbur Dr, Stanford, CA 94305 
e-mail:  
 
Sumit Shah, MD 
875 Blake Wilbur Dr, Stanford, CA 94305 
e-mail:  SAS7@stanford.edu 
 
 
Biostatistician 
 
e-mail:  
  
Study Coordinator: 
 
e-mail:  
 
Study Coordinator: 
Evandro 
 
Email: 
 
IRB-48062                                             OnCore BLDR0028 
     NCT03912818 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................ 7 
1. 
OBJECTIVES ....................................................................................................................... 8 
1.1. 
PRIMARY OBJECTIVE ....................................................................................................... 8 
1.2. 
SECONDARY OBJECTIVES ................................................................................................ 8 
2. 
BACKGROUND .................................................................................................................... 8 
2.1.   
STUDY DISEASE .............................................................................................................. 8 
2.2 
STUDY AGENT DURVALUMAB ......................................................................................... 11 
2.3 
DURVALUMAB BACKGROUND / NON-CLINICAL AND CLINICAL EXPERIENCE ...................... 12 
2.3 
RATIONALE ................................................................................................................... 14 
2.4 
STUDY DESIGN ............................................................................................................. 14 
2.5 
CORRELATIVE STUDIES BACKGROUND ........................................................................... 15 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ................................. 16 
3.1 
ELIGIBILITY CRITERIA AND PARTICIPANT ELIGIBILITY CHECKLIST ..................................... 16 
3.2 
INCLUSION CRITERIA ..................................................................................................... 17 
3.3 
EXCLUSION CRITERIA .................................................................................................... 19 
3.3 
INFORMED CONSENT PROCESS ..................................................................................... 23 
3.4 
STUDY TIMELINE ........................................................................................................... 23 
4. 
TREATMENT PLAN ........................................................................................................... 23 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ................... 31 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 32 
4.3 
ALTERNATIVES .............................................................................................................. 34 
5. 
STUDY AGENT INFORMATION ........................................................................................ 34 
5.1 
STUDY AGENT .............................................................................................................. 34 
6. 
DOSE AND SCHEDULE MODIFICATIONS ....................................................................... 36 
6.1.  DOSE MODIFICATIONS FOR DURVALUMAB .......................................................................... 36 
6.2.  DOSE MODIFICATIONS FOR GEMCITABINE AND CISPLATIN (CIS-GEM) .................................. 37 
6.2.1.  Hematologic Toxicity ................................................................................................ 37 
6.2.2.  Febrile Neutropenia .................................................................................................. 37 
6.2.3.  Kidney Dysfunction .................................................................................................. 37 

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6.2.4.  Liver Dysfunction ...................................................................................................... 37 
6.2.5.  Neurologic Toxicity ................................................................................................... 38 
6.2.6.  Gastrointestinal Toxicity ........................................................................................... 38 
6.2.7.  Other toxicities ......................................................................................................... 38 
6.3.  DOSE MODIFICATIONS FOR CARBOPLATIN AND GEMCITABINE (CARBO-GEM) ....................... 38 
6.3.1.  Hematologic Toxicity ................................................................................................ 38 
6.3.2.  Febrile Neutropenia .................................................................................................. 38 
6.3.4.  Liver Dysfunction ...................................................................................................... 39 
6.3.5.  Neurologic Toxicity ................................................................................................... 39 
6.3.6.  Gastrointestinal Toxicity ........................................................................................... 39 
6.3.7.  Other toxicities ......................................................................................................... 39 
6.4.  DOSE-DENSE METHOTREXATE, VINBLASTINE, DOXORUBICIN, CISPLATIN (DD MVAC) ......... 39 
6.4.1.  Hematologic Toxicity ................................................................................................ 39 
6.4.2.  Kidney Dysfunction .................................................................................................. 39 
6.4.3.  Liver Dysfunction ...................................................................................................... 40 
6.4.4.  Neurologic Toxicity ................................................................................................... 40 
6.4.5.  Gastrointestinal Toxicity ........................................................................................... 40 
6.4.6.  Stomatitis ................................................................................................................. 40 
6.4.7.  Other Toxicities ........................................................................................................ 40 
6.5.  FILGRASTIM (G-CSF) DOSE MODIFICATIONS ...................................................................... 40 
Level 0 ................................................................................................................................. 41 
30 mg/m2 ............................................................................................................................. 41 
Level -1 ............................................................................................................................... 41 
23 mg/m2 ............................................................................................................................. 41 
Level -2 ............................................................................................................................... 41 
15 mg/m2 ............................................................................................................................. 41 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .................................................. 41 
7.1 
POTENTIAL ADVERSE EVENTS ....................................................................................... 42 
7.2 
ADVERSE EVENT REPORTING ........................................................................................ 42 
Reporting of deaths to AstraZeneca ................................................................................... 46 
8. 
CORRELATIVE/SPECIAL STUDIES ................................................................................. 49 
9. 
STUDY CALENDAR BY COHORT (ALL RECEIVE DURVALUMAB) .............................. 52 

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10. 
MEASUREMENTS .......................................................................................................... 58 
10.1  
PRIMARY OUTCOME MEASURES ..................................................................................... 58 
10.2  
SECONDARY OUTCOME MEASURES ................................................................................ 58 
10.2.1  Secondary Outcome Measurement Definition ........................................................ 58 
10.2.2 Secondary Outcome Measurement Methods ........................................................... 58 
10.2.3 Secondary Outcome Measurement Time Points: .................................................... 58 
11. 
REGULATORY CONSIDERATIONS.............................................................................. 58 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL........................................................................... 58 
11.2 
DATA AND SAFETY MONITORING PLAN ........................................................................... 58 
11.3 
DATA MANAGEMENT PLAN ............................................................................................. 59 
12. 
STATISTICAL CONSIDERATIONS ............................................................................... 59 
12.1 
NO INTERIM ANALYSIS IS PLANNED ................................................................................. 59 
12.2.1 
Analysis Population ............................................................................................. 59 
12.2.2  Analysis Plan ........................................................................................................... 59 
12.3  
SAMPLE SIZE ................................................................................................................ 60 
12.3.1 Accrual estimates ..................................................................................................... 60 
12.3.2 Sample size justification ........................................................................................... 60 
12.3.3 Effect size justification .............................................................................................. 60 
12.4 
CRITERIA FOR FUTURE STUDIES ..................................................................................... 60 
13. 
REFERENCES ................................................................................................................ 61 
14.1. APPENDIX 1.  DOSING MODIFICATION AND TOXICITY MANAGEMENT 
GUIDELINES .............................................................................................................................. 64 
14.2. APPENDIX 2.  NATIONAL COMPREHENSIVE CANCER NETWORK BLADDER 
CANCER GUIDELINES .............................................................................................................. 66 

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PROTOCOL SYNOPSIS 
TITLE 
Phase 2 Open Label Study of Durvalumab with Neoadjuvant Chemotherapy 
in Variant Histology Bladder Cancer  
STUDY PHASE 
Phase 2 
INDICATION 
Bladder Cancer with variant histology 
STUDY AGENT 
Durvalumab (MEDI4736), at 750 mg or 1500 mg fixed dose, administered 
intravenously (IV) over 60 minutes.  See Section 4 Treatment Plan for 
exact dose and schedule by cohort.  
OTHER AGENTS 
Chemotherapeutic agents will be administered as an IV infusion according 
to prescribing information or treatment guidance in general use by the 
Investigating site 
Methotrexate 30 mg/m2 on Cycle Day 1  
Gemcitabine 1,000 mg/m2 on Cycle Day 1 (and Cycle Day 8 for some 
cohorts) 
Carboplatin: AUC 5 on Cycle Day 1  
Cisplatin 70 mg/m2 on Cycle Day 1 or 2  
Vinblastine 3 mg/m2 on Cycle Day 2  
Doxorubicin 30 mg/m2 on Cycle Day 2  
See Section 4 Treatment Plan for the exact agents, dose, and schedule by 
cohort.  
Additional supportive care agents, as needed: 
Filgrastim 5 µg/kg subcutaneous (SC)  
Pegfilgrastim 6 mg SQ 
PRIMARY 
OBJECTIVE 
To assess the safety and tolerability of durvalumab in combination with 
chemotherapy in subjects with variant histology bladder cancer 
SECONDARY 
OBJECTIVES 
To determine the percent of subjects post-neoadjuvant 
chemo-immunotherapy who achieve tumor stage of pT2 N0 M0 or better 
(pT1 N0 or pT0) at cystectomy  
• 
To assess the response rate (RR) in post-neoadjuvant chemo 
immunotherapy as assessed by the Investigator using imaging at 
screening and post treatment 
• 
To assess the molecular characterization of tumor tissue 
pre-neoadjuvant therapy and at post-treatment cystectomy (for 
subjects who have persistent disease) 
• 
To determine cell-free DNA at baseline, during treatment and 
following post-treatment cystectomy using Natera platform  

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TREATMENT 
SUMMARY 
This study is designed to evaluate the safety and antitumor activity of the 
combination of durvalumab and chemotherapy for the treatment of subjects 
with variant histology bladder cancer in the neoadjuvant setting. 
All subjects will receive durvalumab, the investigational agent under study, 
administered as an intravenous (IV) infusion on Day 1 of each cycle for a 
total of 4 cycles.  Standard chemotherapy will be administered as an 
IV infusion during each of the 4 cycles.  Choice of standard chemotherapy 
is between the following treatments at the discretion of the treating 
physician: 
• 
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin 
(DD MVAC), in 14-day cycles (2 weeks) 
• 
Cisplatin + Gemcitabine (Cis-Gem), in 21-day cycles (3 weeks)  
• 
Carboplatin + Gemcitabine (Carbo-Gem), in 21-day cycles 
(3 weeks) 
 
The population to be studied includes subjects with newly-identified bladder 
cancer with variant histology. 
ELIGIBILITY 
CRITERIA 
Eligible participants will be cancer patients with histologically-proven 
carcinoma of the bladder of variant urothelial carcinoma histology.  Due to 
length, the Eligibility Criteria are only presented in one instance.  See 
Section 3 Participant Selection and Enrollment Procedures 
SAMPLE SIZE  
24 subjects will be enrolled in this study  
STATISTICAL 
CONSIDERATIONS 
Sample Size Determination: N = 24.  This is a rare population and 
very limited data are available.  
The rich correlative study will allow us to design larger trials in the future 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
ADL 
Activities of daily living 
AE 
Adverse event 
BP 
Blood pressure 
BSA 
Body surface area 
CBC 
Complete blood count 
cfDNA 
Circulating free DNA OR cell-free DNA 
ctDNA 
Circulating tumor DNA  
Carbo-Gem 
Carboplatin + gemcitabine  
CI 
Confidence interval 
Cis-Gem 
Cisplatin + gemcitabine  
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DD MVAC 
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin  
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertensions 
IDS 
Stanford Investigational Drug Service  
IRB 
Institutional Review Board 
IP 
Investigational Product 
IV 
Intravenous 
LLN 
Lower limit of normal  
MIBC 
Muscle invasive bladder cancer 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression-free survival  
PR 
Partial response 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SC 
Subcutaneous  
SD 
Stable disease 
SOC 
Standard of care  
TTP 
Time-to-progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 

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1. 
OBJECTIVES 
1.1. 
Primary Objective  
• 
To assess the safety and tolerability of durvalumab in combination with 
chemotherapy in subjects with variant histology bladder cancer 
1.2. 
Secondary Objectives 
 
• 
To determine the percent of subjects post-neoadjuvant 
chemo-immunotherapy who achieve tumor stage of pT2 N0 M0 or better 
(pT1 N0 or pT0) at cystectomy  
• 
To assess the response rate (RR) in post-neoadjuvant chemo 
immunotherapy as assessed by the Investigator using imaging at screening 
and post treatment 
• 
To assess the molecular characterization of tumor tissue pre-neoadjuvant 
therapy and at post-treatment cystectomy (for subject who have persistent 
disease) 
• 
To determine circulating free DNA (cfDNA) (alternate term “cell-free DNA”) at 
baseline, during treatment and following post-treatment cystectomy using 
Natera platform  
2. 
BACKGROUND 
2.1.   Study Disease 
It is estimated that there will be 74,690 new cases and 15,580 deaths from bladder cancer in the 
United States in 2018.  The majority of cases are non-muscle invasive and are treated by 
cystoscopic resection, with or without intravesical medical therapy instilled directly into the 
bladder.  For those with muscle-invasive disease, therapy consisting of a radical cystectomy or 
definitive radiation therapy is indicated.  Even with these radical treatments, the mortality from 
muscle- invasive bladder cancer remains high.  Despite the survival advantage associated with 
its use, neoadjuvant chemotherapy remains poorly utilized in general medical practice in the 
United States.  One explanation for the low utilization of neoadjuvant chemotherapy is the 
concern that some patients with surgically curable disease will become chemotherapy-resistant 
and may progress during treatment with neoadjuvant chemotherapy, thus be rendered 
incurable.  This protocol will examine the utility of neoadjuvant chemotherapy combined with 
durvalumab in subjects with variant histology bladder cancer. 
Chemotherapy for Bladder Cancer 
The mainstay of contemporary, cytotoxic chemotherapy for advanced bladder cancer has been 
cisplatin-based combination therapy.  MVAC chemotherapy was designed in the mid 1980’s and 
came into general use in the 1990’s.  (Sternberg, 1985) When compared to single-agent 
cisplatin, MVAC was associated with improved response rates and survival, although the 
regimen produced notable toxicity, mainly hematologic, gastrointestinal and infectious.  The 
doublet of gemcitabine and cisplatin was later recognized to also have significant activity 
against urothelial cancer.  In a randomized, phase 3 study, 405 subjects with Stage IV 
transitional cell carcinoma were given MVAC vs Cis-Gem.  (Von der Maas, 2008) The response 
rates between the arms were similar (Cis-Gem, 49%;  MVAC 45%) as was the overall and 

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progression-free survival (PFS).  The side effects, especially those related to bone marrow 
suppression (neutropenic fever:  1% for Cis-Gem; 12% for MVAC), were greater in the MVAC 
arm as compared to Cis-Gem-treated subjects.  The long-term results of this study have been 
reported with a median overall survival (OS) of 14.0 months with Cis-Gem vs 15.2 months with 
MVAC (p = 0.66).  
In the phase 3 trial of Cis-Gem vs MVAC, Cis-Gem was given on a 28-day schedule, the same 
duration as the traditional MVAC cycle.  In regimens utilizing a 28-day cycle of Cis-Gem, 
gemcitabine is given on Days 1, 8, and 15, although the Day 15 dose is oftentimes delayed or 
skipped due to bone marrow suppression, notably thrombocytopenia.  With this recognition, a 
21-day Cis-Gem regimen, with gemcitabine given on Days 1 and 8 only, was investigated.  In 
one retrospective analysis, 212 subjects with Stage IV transitional cell carcinoma were treated 
with either 21- or 28-day.  The response rate between the 2 schedules was similar, with an 
overall response rate of 59.7% with the 3-week and 55.6 % with the 4-week regimen; the 
complete response rate was 21% in both arms.  Treatment compliance was improved with the 
21-day schedule; with only 19% requiring dose modification in the 21-day arm, vs 62% in the 
28-day group, with 47% in the latter required to omit Day15 gemcitabine.  The rate of febrile 
neutropenia in the 21-day arm of this study was less than 10%.  A smaller, single arm study of 
21-day Cis-Gem in 27 bladder cancer patients demonstrated a strong overall response rate of 
48% without any Grade 4 toxicity or treatment-related death.  In addition, a randomized study of 
107 patients with mixed cancer types (predominately lung cancer) examined the safety and 
efficacy of 21- vs 28-day Cis-Gem.  (Soto, Ann Oncol, 2002)  The 3-week schedule was better 
tolerated, with less Grade 3/4 thrombocytopenia (29.5% vs 5.5%) and less delays or dose 
reductions (51% vs 19%).  Only the lung cancer patients were analyzed for response rate, since 
they represented the majority of the enrolled subjects, and these rates were similar between the 
arms.  In summary, even though the randomized phase 3 trial of Cis-Gem vs MVAC used 
28-day Cis-Gem schedule, subsequent studies have reported improved tolerance, dose-density 
and preserved efficacy with 21-day Cis-Gem.  
In a parallel fashion, efforts were undertaken to improve the tolerability and dose-density of 
MVAC.  Early reports of the use of hematologic growth factor support found that dose escalation 
of MVAC in urothelial carcinoma patients was possible and such an approach was associated 
with a favorable response rate.  With this emerging information, Sternberg, et al pursued a 
randomized phase 3 trial of high-dose intensity MVAC with granulocyte colony-stimulating factor 
(G-CSF) vs traditional MVAC in 263 advanced urothelial patients.  (Sternberg Ann Oncol, 1993) 
There was a complete response rate (CRR) of 21% and an overall response rate (ORR) of 62% 
with high-dose MVAC, compared to a CRR or 9% and ORR of 50% with standard-dose MVAC; 
the p value for the CR difference was 0.009.  Neutropenic fever was more common with 
standard-dose MVAC (26% vs 10%), although this may be attributed to the disproportionate use 
of GCSF on the high-dose (94%) compared to the standard-dose (19%).  In an updated report, 
with 7 years of follow-up, 24.6% were alive in the high-dose, vs 13.2% in the standard-dose 
MVAC arms.  (Sternberg, Eur J Cancer, 2006) While the median survival was similar between 
the 2 groups (15.1 vs 14.9 months), the overall mortality hazard ratio (HR) did favor high-dose 
MVAC (0.76; 95% CI, 0.58 to 0.99).  Taken together, high- dose MVAC allows for more dose 
density, with lower toxicity and improved markers of efficacy.  
317 subjects with T2-T4aNxM0 urothelial carcinoma of the bladder were randomized to 3 cycles 
of cisplatin and methotrexate vs no neoadjuvant chemotherapy.  (Grossman NEJM, 2003) The 

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rate of complete pathologic response (pT0) was higher in the chemotherapy group (26.4%) 
compared to the non-chemotherapy group (11.5%) (p = 0.001), with the pT0 finding in the 
control arm likely attributable to complete transurethral resection of the tumor pre-operatively.  
The 5-year overall survival (OS) was improved in absolute terms by 7%, from 46% to 53%, with 
neoadjuvant chemotherapy, although this was not statistically significant in this relatively small 
study.  With these and several other small randomized trials available, a meta-analysis of 
platinum-based neoadjuvant chemotherapy in patients with muscle- invasive bladder cancer 
was published in 2003.  This work found a significant survival benefit with neoadjuvant 
chemotherapy, yielding a HR of 0.87 (95% CI, 0.78 to 0.98).  A second meta- analysis on this 
topic was performed in 2004 and included 8 randomized trials of cisplatin combination 
neoadjuvant therapy, with a pooled HR for OS of 0.87 (95% CI, 0.78 to 0.96).  This work also 
noted that a major pathologic response was associated with OS in 4 trials, supporting the use of 
pT0 rates as a marker of survival.  
Two randomized studies were launched in the late 1980’s to specifically assess the utility of 
MVAC and CMV chemotherapy in the neoadjuvant bladder cancer setting, as these regimens 
emerged as more effective than single-agent cisplatin.  SWOG 8710 enrolled 317 subjects with 
T2-T4aN0M0 bladder cancer, randomizing subjects to 3 cycles of standard-dose (28-day) 
MVAC vs no chemotherapy before cystectomy.  The median survival was improved in the 
experimental arm (77 vs 44 months) with a p = 0.06, favoring chemotherapy.  The proportion of 
subjects with a pT0 at the time of surgery was also increased in the MVAC arm, 38% vs 15% (p 
< 0.001).  In an important post-hoc analysis of SWOG 8710, the significance of mixed histology 
(pure urothelial carcinoma versus a proportion of urothelial carcinoma) was analyzed.  Among 
those with mixed tumors, there was a clear survival advantage (HR 0.46; 95% CI, 0.25 to 0.87), 
supporting the use of neoadjuvant, cisplatin-based chemotherapy in those with a component of 
squamous or glandular differentiation in addition to urothelial carcinoma in their tumor.  
A second, European-led neoadjuvant study was larger and enrolled 976 subjects with T2 
(Grade 3), T3-T4a N0M0 urothelial cancer of the bladder in subjects planning for either 
cystectomy or definitive external beam radiation therapy.  (Lancet, 1999) Participants were 
randomized to a 21-day cycle of cisplatin-methotrexate-vinblastine (CMV) chemotherapy for 
3 cycles versus no chemotherapy.  For the 417 subjects undergoing cystectomy, the pathologic 
response rate (pT0 at the time of surgery) was 32.5% with chemotherapy vs 12.3% without.  An 
update of the survival results was subsequently published with 8 years of follow-up.  Combining 
both the radiation and surgery groups, neoadjuvant chemotherapy was associated with a 16% 
reduction in the risk of death (HR, 0.84; 95% CI, 0.72 to 0.99) and an improvement in the 
10-year survival from 30% to 36%.  Considering the surgical cystectomy subjects alone, the 
reduction in the risk of death was 26% (HR, 0.74; 95% CI, 0.57 to 0.96; p = 0.022).  
As noted, since the initiation of these phase 3 neoadjuvant studies of MVAC and CMV 
chemotherapy, Cis-Gem has become a standard approach in advanced urothelial carcinoma, 
frequently favored over the more toxic MVAC regimen.  There is a limited amount of clinical data 
for the use of Cis-Gem in the neoadjuvant setting.  In one report from investigators at Memorial 
Sloan-Kettering, the results of 42 bladder cancer patients given 21-day neoadjuvant Cis-Gem 
was reported and compared historical controls given MVAC.  The pT0 proportion was 26% with 
Cis-Gem, compared to 28% with the historical MVAC group.  They also assessed < pT2 rate, 
which was 36% with Cis-Gem, vs 35% with MVAC.  

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The prognostic importance of the pathologic T staging pT0 at the time of radical cystectomy is 
associated with long-term and survival outcomes in bladder cancer patients.  In the SWOG 
8710 trial, regardless of treatment arm, the finding of pT0 at the time of surgery correlated with 
survival.  (Grossman NEJM, 2003) In a subsequent analysis, the impact of pT0 vs < pT2 (pT0, 
pTa, pTis, and pT1) on survival was analyzed.  In the chemotherapy arm, pathologic findings of 
< pT2 was observed in 44%, with 30% having pT0.  The pT0 rate is lower in this analysis 
compared to the original New England Journal of Medicine publication, as patients who did not 
actually receive any chemotherapy were also included.  Those with pT0 had a median OS of 
13.6 years, those with pT1/pTis/pTa had a median OS of 10.6 years, while those with pT2 or 
great disease at surgery had a median OS of just 3.7 years. (Sonpavade Cancer, 2009)  The 
impact of pathologic stage on long-term outcomes were also evaluated in 2230 patients with 
radical cystectomy, but no adjuvant chemotherapy.  They found 5.1% had pT0 at the time of 
surgery; with a median follow-up of 48 months, 10.1% of these pT0 patients had recurrent 
disease.  Of note, the recurrence-free outcomes were similar between the pT0 and pTa/pTis 
patients (p = 0.557).  Taken together, these data suggest the prognostic significance of both 
pT0 and < pT2 at the time of cystectomy.  
Carboplatin-based chemotherapy has shown to be inferior to cisplatin-based chemotherapy in 
the metastatic setting.  In general, if patients have abnormal creatinine that does not allow 
cisplatin-based chemotherapy they undergo cystectomy rather than neoadjuvant chemotherapy.  
Based on the rarity of the data in variant histology we will allow patients to get carboplatin-based 
chemotherapy if creatinine clearance < 50cc. 
2.2 
Study Agent Durvalumab  
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors.  (Dunn, 2004) 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation.  The PD-1 receptor (CD279) is expressed on the surface of activated T cells (Keir, 
et al, 2008).  It has 2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) 
(Okazaki and Honjo, 2007).  The PD-1 and PD-L1/PD-L2 belong to the family of immune 
checkpoint proteins that act as co-inhibitory factors, which can halt or limit the development of 
T cell response.  When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T cell, 
which reduces cytokine production and suppresses T-cell proliferation.  Tumor cells exploit this 
immune checkpoint pathway as a mechanism to evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin, et al, 2016).  
Importantly, PD-L1 is commonly over-expressed on tumor cells or on non-transformed cells in 
the tumor microenvironment (Pardoll, 2012).  PD-L1 expressed on the tumor cells binds to PD-1 
receptors on the activated T-cells leading to the inhibition of cytotoxic T cells.  These 
deactivated T-cells remain inhibited in the tumor microenvironment.  The PD-1/PD-L1 pathway 
represents an adaptive immune resistance mechanism that is exerted by tumor cells in 
response to endogenous anti-tumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination.  The binding of an anti–PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells.  This activity overcomes PD-L1–mediated inhibition of antitumor immunity.  While 

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functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different 
from direct agonism of a stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers.  Based on these findings, an anti–PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients with 
cancer.  Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting 
the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety 
profile, supporting the hypothesis that an anti–PD-L1 antibody could be used to therapeutically 
enhance antitumor immune response in cancer patients (Brahmer, 2012;  Hirano, 2005;  
Iwai, 2002;  Okudaira, 2009;  Topalian, 2012;  Zhang, 2008) with responses that tend to be 
more pronounced in patients with tumors that express PD-L1(Powles, 2014; Rizvi, 2015, 
Segal, 2015) .  In addition, high mutational burden (eg, in bladder carcinoma) may contribute to 
the responses seen with immune therapy. 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively expressed 
by regulatory T cells and upregulated on activated T cells.  CTLA-4 delivers a negative 
regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on 
antigen-presenting cells (Fife, 2008).  Blockade of CTLA-4 binding to CD80/86 by anti–CTLA-4 
antibodies results in markedly enhanced T-cell activation and antitumor activity in animal 
models, including killing of established murine solid tumors and induction of protective antitumor 
immunity.  Therefore, it is expected that treatment with an anti–CTLA-4 antibody will lead to 
increased activation of the human immune system, increasing antitumor activity in patients with 
solid tumors. 
Pre-clinical data have now been added to with a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and 
programmed death ligand 1 (PD-L1) has promising clinical activity.  Ipilimumab was granted 
United States (US) Food and Drug Administration (FDA) approval for the treatment of metastatic 
melanoma and is currently under investigation for several other malignancies, whilst nivolumab 
and pembrolizumab, two anti–PD-1 agents, and atezolizumab, an anti–PD-L1, agent have been 
granted approvals by agencies such as the US FDA and the European Medicines Agency 
approval for the treatment of a number of malignancies including metastatic melanoma, 
squamous and non-squamous cell non-small-cell lung cancer and urothelial carcinoma.  In 
addition, there are data from agents in the anti–PD-1/PD-L1class showing clinical activity in a 
wide range of tumor types. 
2.3 
Durvalumab Background / Non-Clinical and Clinical Experience 
The non-clinical and clinical experience is fully-described in the most current version of the 
durvalumab Investigator’s Brochure.  
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for 
use in the treatment of cancer (MedImmune is a wholly-owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). The 
proposed mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 
with PD-1 and CD80 (B7.1).  Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases 
the inhibition of immune responses, including those that may result in tumor elimination.  In vitro 
studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary 
human T cells resulting in the restored proliferation of IFN-γ (Stewart, et al, 2015).  In vivo 

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studies have shown that durvalumab inhibits tumor growth in xenograft models via a 
T-cell-dependent mechanism (Stewart, et al, 2015).  Based on these data, durvalumab is 
expected to stimulate the subject’s antitumor immune response by binding to PD-L1 and shifting 
the balance toward an antitumor response.  Durvalumab has been engineered to reduce 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.  
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies 
either as monotherapy or in combination with other anti-cancer agents.  Refer to the current 
durvalumab Investigator’s Brochure for a complete summary of non-clinical and clinical 
information including safety, efficacy and pharmacokinetics.  
PK/Pharmacodynamic Data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition.  The PK approached 
linearity at ≥ 3 mg/kg Q2W, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the durvalumab dosing frequency can be adapted to a 
particular regimen given the linearity seen at doses higher than 3 mg/kg.  The expected half-life 
with doses ≥ 3 mg/kg Q2W is approximately 21 days.  A dose-dependent suppression in 
peripheral sPD-L1 was observed over the dose range studied, consistent with engagement of 
durvalumab with PD-L1.  A low level of immunogenicity has been observed.  No patients have 
experienced immune-complex disease following exposure to durvalumab.  
A population PK model was developed using the data from Study 1108 (doses 0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W (Fairman, 2014).  Multiple simulations indicate that a similar overall 
exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as 
represented by AUCss (4 weeks).  Median Cmax,ss is expected to be higher with 20 mg/kg Q4W 
(~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 fold).  
Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to be consistent with 
10 mg/kg Q2W with the proposed similar dose of 20 mg/kg Q4W expected to (a) achieve 
complete target saturation in majority of patients; (b) account for anticipated variability in PK, 
pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain sufficient PK 
exposure in case of ADA impact; and (d) achieve PK exposure that yielded maximal antitumor 
activity in animal models. 
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both 
regimens maintain complete sPD-L1 suppression at trough, and the available clinical data, the 
20 mg/kg Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety 
profiles, supporting further development with a dose of 20 mg/kg Q4W.  
Clinical Data 
The current durvalumab Investigator’s Brochure is available for a complete summary of clinical 
information including safety, efficacy and pharmacokinetics at the 20 mg/kg Q4W regimen. 
Rationale For 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).  

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Population PK analysis indicated only minor impact of body weight (WT) on the PK of 
durvalumab (coefficient of ≤ 0.5).  The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model.  A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg).  A 
total of 1000 patients were simulated using body WT distribution of 40–120 kg.  Simulation 
results demonstrate that body WT-based and fixed dosing regimens yield similar median steady 
state PK concentrations with slightly less overall between-patient variability with fixed dosing 
regimen.  
Similar findings have been reported by others (Ng, 2006, Wang, 2009, Zhang, 2012, 
Narwal, 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 (Wan, 2009)].  In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-patient 
variability in pharmacokinetic/pharmacodynamics parameters (Zhang, 2012).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens.  Based on average body WT of 75 
kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the 
current study. 
Durvalumab is FDA-approved for the treatment of bladder cancer.  This study is planned to be 
conducted as IND-exempt. 
2.3 
Rationale 
Neoadjuvant chemotherapy followed by cystectomy is standard of care in patients with 
newly-diagnosed urothelial cancer of the bladder; outcome in patients with variant histology is 
less well known.  
Patients achieving a pT0 or < T2 following neoadjuvant chemotherapy have good outcomes 
with low risk of relapse.  The likelihood of achieving > pT2 is 30% with cisplatin-based 
chemotherapy in patients with classic urothelial cancer and variable with “variant histology” 
group.  Patients with variant histology need better combination therapies to increase the rate of 
pT0 or < pT2.  
Rationale for Dose Selection: The standard dosing chemotherapy regimens that have been well 
established and described previously along with standard dose of durvalumab will be used in 
this study.  Given that the timing of chemotherapy is variable in the 3 regimens selected 
durvalumab will be dosed at 750 mg day 1 of each cycle for DD MVAC and 1500 mg in the 
cis/gem and carbo/gem arms. 
2.4 
Study Design 
This study is designed to evaluate the safety and antitumor activity of the combination of 
durvalumab and chemotherapy for the treatment of subjects with variant histology bladder 
cancer in the neoadjuvant setting.  Variant bladder cancer histologies include:  squamous 
differentiation; glandular differentiation; nested variant; microcystic variant; micropapillary 
variant; lymphoepithelioma-like carcinoma; plasmacytoid and lymphoma-like variants; 

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sarcomatoid variant/carcinosarcoma; giant cell variant; trophoblasitic differenetation; clear cell 
variant; lipid cell variant; and undifferentiated carcinoma. This is a single arm open label 
non-randomized trial with the primary objective to assess the safety and tolerability of 
durvalumab in combination with chemotherapy in subjects with variant histology bladder cancer.  
Secondary objectives include determining the percent of subjects post-neoadjuvant 
chemo-immunotherapy who achieve tumor stage of pT2 N0 M0 or better (pT1 N0 or pT0) at 
cystectomy; assessing the molecular characterization of tumor tissue pre-neoadjuvant therapy 
and at post-treatment cystectomy (for subjects with have persistent disease); and to determine 
cell-free DNA at baseline, during treatment and following post-treatment cystectomy using 
Natera platform.  
All subjects will receive durvalumab, the investigational agent under study, administered as an 
intravenous (IV) infusion on Day 1 of each cycle in combination with neoadjuvant 
chemotherapy.  Subjects will be treated for 4 cycles of durvalumab and chemotherapy followed 
by cystectomy. 
Response will be assessed by pathological staging post-cystectomy.  
2.5 
Correlative Studies Background 
Recent work has suggested that transitional bladder cancer, has a complex mutational 
signature including on average 300 exonic mutations, 200 segmental alterations, and 22 
genomic rearrangements (Nature.  20 March 2014;507:315 to 322 ).  Genomic instability is a 
hallmark of cancer, with recent studies suggesting that DNA repair pathway dysregulation is 
common across multiple cancer types (Lawrence, et al, Nature, 2014).  Germline and / or 
somatic alterations in pathways controlling homologous recombination, microsatellite instability, 
and non-homologous end joining have been implicated across multiple cancer types, most 
notably breast and ovarian cancer (Aleshin, et al, Current Breast Cancer Reports, 2017).  In 
urothelial bladder cancer, upwards of 10% of cases have been shown to have defects in 
homologous recombination pathways (Heeke, et al, ASCO, 2017).  There is also early evidence 
to suggest patients with defective DNA repair pathways are most likely to benefit from platinum- 
based chemotherapy (Bellmunt, et al, Ann Onc, 2007, Van Allen, et al, Cancer Disco, 2014).  
However, comprehensive assessment on the genomic landscape of bladder cancer with “variant 
histology” is lacking, and even less is known about predictive biomarkers associated with 
treatment response.  
Measurement of tumor-specific mutations in plasma and urine is emerging as a powerful tool for 
cancer treatment and recurrence monitoring.  Circulating tumor DNA (ctDNA) is released into 
circulation and can be recovered from a variety of body fluids, including plasma and urine (Wan, 
et al, Nat Rev Cancer, 2017).  Previous work has suggested that ctDNA is detectable in patients 
with bladder cancer and that rising levels of ctDNA are associated with disease progression and 
early detection of metastatic relapse (Kirkenkamp, et al, Eur Urology, 2017).  Furthermore, 
novel ctDNA measurement techniques allow for creation of personalized probe sets that allow 
for serial measurement of both clonal and subclonal mutations during and after definitive 
treatment (abbosh, et al, Nature, 2017).  
In this study we propose corelative studies including whole exome sequencing on tissue to 
characterize the genomic landscape of bladder cancer with “variant histology.”  Furthermore, 
sequential plasma collection will be used to characterize the evolution of subject-specific 
circulating tumor DNA (ctDNA) signatures, as well as, evaluate early plasm- based markers of 

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disease resistance and relapse.  We will also analyze tumor mutational burden and correlate 
that to response 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Eligibility Criteria and Participant Eligibility Checklist 
Inclusion and Exclusion Criteria are provided on the Eligibility Checklist, following, and which 
may be extracted for use in screening potential subjects.  
The following Participant Eligibility Checklist will be completed in its entirety for each subject 
prior to start of Cycle 1 Day 1.  The completed, signed, and dated checklist will be retained in 
the subject’s study file.  
Pursuant to Stanford Medicine SOP “Confirmation of Participant Eligibility in Clinical Trials,” the 
treating Physician (investigator); the Study Coordinator; and an Independent Reviewer will verify 
that the subject’s eligibility is accurate; complete; and legible in source records.  A description of 
the eligibility verification process will be included in the EPIC or other Electronic Medical Record 
progress note.  

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Participant Eligibility Checklist 
For each prospective study participant that is screened, this checklist will be printed, the results 
recorded, and filed in the respective subject binder or file.  It is anticipated that not all 
prospective study participants will be enrolled.  
I. 
Protocol Information  
Protocol Title: 
Phase 1-2 Open Label Study of Durvalumab with Neoadjuvant 
Chemotherapy in Variant Histology Bladder Cancer 
eProtocol number: 
OnCore number: 
IRB-48062 
BLDR0028 Amendment 2 
Principal 
Investigator: 
Sandy Srinivas, MD  
II. 
Subject Information  
Subject ID:  SCI - __ __ __ 
Regimen Type:        
 DD MVAC              
 Cis/Gem        
 Carbo/Gem       
Gender  
  Male   
 Female   
III. 
Study Information  
3.2 
Inclusion Criteria 
Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
1. Signed Informed Consent  
 
 
 
2. Age ≥ 18 years at time of study entry 
 
 
 
3. Eastern Collaborative Oncology Group (ECOG) 
Performance Status score of 0 or 1 
 
 
 
4. Body weight > 30kg  
 
 
 

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Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
5. Adequate hematologic and organ function within 28 days 
before the first study treatment, defined using the following: 
• 
Absolute neutrophil count (ANC) ≥ 1500 mm3 
• 
Hemoglobin ≥ 9.0 g/dL   
• 
Platelet count ≥ 100,000 per mm3 
• 
Serum bilirubin ≤ 1.5 × upper limit of normal (ULN).  
Subjects with Glibert’s syndrome will be considered after 
consultation with the PI.  
• 
Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 × ULN 
• 
For subjects who will be treated with DD MVAC or Cis-
Gem, creatinine clearance ≥ 50 mL/min as measured 
based on Cockroft-Gault glomerular filtration rate estimation 
• 
For subjects who will be treated with Carbo-Gem, creatinine 
clearance ≥ 30 mL/min as measured based on 
Cockroft-Gault glomerular filtration rate estimation 
Cockcroft-Gault Equation 
Males:    (140 – age) × (weight in Kg) 
             72 × (serum Creatinine) 
 
Females:  (140 – age) × (weight in Kg) × 85 
           72 × (serum Creatinine) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 N/A (Carbo subject) 
 
 N/A (Cis subject) 
6. Anticipated life expectancy of ≥ 12 weeks as assessed by 
the Investigator 
 
 
 
7. Histologically-proven carcinoma of the bladder of variant 
urothelial carcinoma histologies which include squamous, 
adenocarcinoma, nested, plasmacytoid, micropapillary, 
glandular differentiation, lipid cell, clear cell, 
undifferentiated, giant cell, trophoblastic, sarcomatoid, 
carcinosarcoma; subjects with mixed cell types are eligible 
 
 
 
8. Stage cT2-T4a, N0-N1, M0 disease.  Clinical T stage is 
based on the TURBT sample and imaging studies.  
Subjects must undergo cystoscopy and TURBT as part of 
screening within 60 days prior to start of Cycle 1 Day 1 
 
 
 
9. Abdominal/pelvic imaging by CT or MRI scan; chest 
imaging by CT scan or x-ray (CT/PET) within 30 days prior 
to start of Cycle 1 Day 1 
 
 
 
10. Resting 12-lead electrocardiogram (ECG) documenting 
QTcF ≤ 470 ms  
 
 
 
11. Must provide a formalin-fixed paraffin-embedded (FFPE) 
tissue block and 1 H&E slide (preferred) or one of the 
following: 
  •  10 unstained slides and 1 H&E slide OR 
  •  Tissue block punches and 1 H&E slide, OR 
  •  4 to 6 cores and 1 H&E slide 
 
 
 

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Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
12. Willing and able to comply with the protocol for the duration 
of the study including undergoing treatment, scheduled 
visits and examinations including follow up. 
 
 
 
13. For Female Subjects: 
•  Women < 50 years of age would be considered 
post-menopausal if they have been amenorrheic for 
12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone 
and follicle-stimulating hormone levels in the 
post-menopausal range for the institution or underwent 
surgical sterilization (bilateral oophorectomy or 
hysterectomy).  
•  Women ≥ 50 years of age would be considered 
post-menopausal if they have been amenorrheic for 
12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause 
with last menses > 1 year ago, had chemotherapy-induced 
menopause with last menses > 1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
 
 
 N/A (male subject) 
3.3 
Exclusion Criteria 
Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
1. Prior treatment with systemic cytotoxic chemotherapy for 
muscle invasive bladder cancer (MIBC) 
 
 
 
2. For Carboplatin patients only: Class III or IV heart failure, 
according to New York Heart Association Classifications  
 
 
 N/A (non-carbo subject) 
3. For Cisplatin patients only: Left ventricular ejection fraction 
of less than normal 
 
 
 N/A (non-cis subject) 
4. Administration of an investigational therapeutic agent within 
28 days of protocol start of Cycle 1 Day 1 
 
 
 
5. Current participation in a trial using an investigational 
agent.  Subjects may participate in non-interventional, 
observational studies 
 
 
 
6. Prior treatment with an anti-PD1 or anti-PDL1 inhibitor 
including durvalumab 
 
 
  
7. Receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone or equivalent per day 
within 7 days prior to the first dose of study treatment) 
 
 
 

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Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
8. History of another malignancy within 5 years before the first 
dose of study drug, or any evidence of residual disease 
from a previously diagnosed malignancy.  Subjects with the 
following are allowed on study: 
• 
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 
 
 
 
9. 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.  The following 
are exceptions to this criterion: 
a. Intranasal, inhaled, topical steroids, or local steroid 
injections (eg, intra articular injection) 
b. Systemic corticosteroids at physiologic doses not to 
exceed 10 mg/day of prednisone or its equivalent 
c. Steroids as premedication for hypersensitivity reactions 
(eg, CT scan premedication) or anti emetic during 
chemotherapy 
 
 
 
10.  History of allogenic organ transplantation 
 
 
 
11.  Active or prior documented autoimmune or inflammatory 
disorders (including inflammatory bowel disease [eg, colitis 
or Crohn's disease]), diverticulitis (with the exception of 
diverticulosis), systemic lupus erythematosus, Sarcoidosis 
syndrome, or Wegener syndrome (granulomatosis with 
polyangiitis, Graves' disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc).  The following are exceptions to 
this criterion: 
a. Subjects with vitiligo or alopecia 
b. Subjects with hypothyroidism (eg, following Hashimoto 
Syndrome) stable on hormone replacement 
c. Any chronic skin condition that does not require 
systemic therapy 
d. Subjects with celiac disease controlled by diet alone 
 
 
 
12. Uncontrolled intercurrent illness, including but not limited to, 
ongoing or active infection, symptomatic congestive heart 
failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or 
psychiatric illness/social situations that would limit 
compliance with study requirement, substantially increase 
risk of incurring AEs or compromise the ability of the 
subject to give written informed consent 
 
 
 
13.  History of active primary immunodeficiency 
 
 
 

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Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
14.  Active infection including: 
• 
Tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and 
TB testing in line with local practice) 
 
• 
Hepatitis B (positive HBV surface antigen (HBsAg) result) 
Subjects with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [anti-HBc] and absence of 
HBsAg) are eligible.   
 
• 
Hepatitis C  
Subjects positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA 
 
• 
Human Immunodeficiency Virus (positive HIV 1/2 
antibodies).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. Receipt of live attenuated vaccine within 30 days prior to 
the first dose of Study medication.  Note:  Subjects, if 
enrolled, should not receive live vaccine whilst receiving 
study medication and up to 30 days after the last dose of 
study medication 
 
 
 
16. Pregnant or lactating   
 
 
 N/A (male subject) 
17. Male or female subject of reproductive potential who are 
not willing to employ effective birth control from screening 
to 90 days after the last dose of durvalumab  
 
 
 
18. Known allergy or hypersensitivity to any of the study 
medications or any of the study medication excipients 
 
 
 
19. Judgment by the investigator that the subject is unsuitable 
to participate in the study and the subject is unlikely to 
comply with study procedures, restrictions and 
requirements 
 
 
 
* All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.  

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V. 
Statement of Eligibility  
By signing this form of this trial I verify that this subject is:  
 eligible / 
 ineligible for 
participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the IRB of record, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.  
 
Study Coordinator printed name: 
Date:  
Signature: 
 
Investigator printed name: 
Date:  
Signature: 
 
Triple-check reviewer printed name: 
Date:  
Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants or the 
participant’s legally authorized representative must sign the IRB approved informed consent 
prior to participation in any study-specific procedure.  The participant must receive a copy of the 
signed and dated consent document.  The original signed copy of the consent document must 
be retained in the medical record or research file.  
 
3.4 
Study Timeline 
Primary Completion 
The study is expected to reach the primary completion date 30 months from the time the first 
subject is treated on the study. 
Study Completion 
It is estimated that the study will reach completion 36 months from the time the first subject is 
treated on the study.  
 
4. 
TREATMENT PLAN 
Screening Visit (Day -30 to Day 1) 
The following will be conducted at the screening visit. 
• 
Informed consent 
• 
Medical history and demographics 
• 
Review of prior and concomitant medications 
• 
Initial collection of tumor specimen for genomic sequencing (Natera) 
• 
Blood sample for cell-free DNA (cfDNA) 
• 
CT or MRI abdomen/pelvis preferable.  PET-CT for subjects with impaired renal 
function is an acceptable alternative.   
• 
CT or X-ray of chest  
• 
Bone scan is necessary if bone metastases are suspected (elevated alkaline 
phosphatase). 
• 
Vital signs, weight and height 
• 
Physical exam 
• 
ECOG performance status 
• 
12-lead ECG  
• 
CBC with differential 

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• 
Comprehensive metabolic panel (Magnesium is to be performed at baseline on Day 
1 and as clinically indicated) 
• 
Serology for hepatitis B 
• 
Serology for hepatitis C 
• 
Serology for Human Immunodeficiency Virus   
• 
TSH 
• 
Coagulation (PT, PTT, INR) 
• 
Creatinine clearance 
• 
Urinalysis 
• 
Serum pregnancy test (for women of childbearing potential only) 
• 
Study eligibility per inclusion/exclusion criteria 
 
Treatment Period Assessments, all cohorts, for each cycle (Cycles 1 to 4) 
For DD MVAC Cohort ONLY, pre-dose on Day 1, and on Day 2 
• 
Vital signs  
• 
Physical exam (only on Day 1 of each Cycle)  
• 
ECOG performance status (only on Day 1 of each Cycle) 
• 
CBC with differential 
• 
Comprehensive metabolic panel 
For Cis-Gem & Carbo-Gem Cohorts ONLY, pre-dose on Day 1, and on Day 8 
• 
Vital signs  
• 
Physical exam (only on Day 1 of each Cycle)  
• 
ECOG performance status (only on Day 1 of each Cycle) 
• 
CBC with differential 
• 
Comprehensive metabolic panel 
 
Treatment Administration per Cycle 
• DD MVAC Cohort:   Durvalumab + Dose-dense Methotrexate, Vinblastine, 
Doxorubicin, Cisplatin (DD MVAC) 
 
IMPORTANT CLINICAL NOTE:  
Durvalumab dose for DD MVAC   
*DIFFERS*  from Cis-Gem or Carbo-Gem 

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Treatment with Durvalumab plus DD MVAC is on a 14-day cycle as described below: 
On Day 1 of each 14-day cycle, the following treatments will be administered as IV infusions: 
• 
Durvalumab at a fixed dose of 750 mg administered IV over approximately 
60 minutes on Day 1 of each cycle 
Chemotherapeutic agents will be administered as an IV infusion according to prescribing 
information or treatment guidance in general use by the Investigating site: 
• 
Methotrexate at a fixed dose of 30 mg/m2 IV on Day 1 of each cycle 
On Day 2 of each 14-day cycle.  The following treatments will be administered as an IV infusion: 
• 
Vinblastine 3 mg/m2 IV on Day 2 of each cycle 
• 
Doxorubicin 30 mg/m2 IV on Day 2 of each cycle 
• 
Cisplatin 70 mg/m2 IV on Day 2 of each cycle 
Additionally, the following supportive care will be administered as needed: 
• 
Filgrastim 5 µg/kg by subcutaneous (SC) administration per institutional SOC  
(alternative to filgrastim:  Pegfilgrastim 6 mg SC per institutional SOC) 
 
• Cis-Gem Cohort:  Durvalumab plus Cisplatin + Gemcitabine  
 
Treatment with Durvalumab plus Cis-Gem is on a 21-day cycle as described below: 
On Day 1 of each 21-day cycle, the following treatments will be administered as an IV infusion: 
• 
Durvalumab at a fixed dose of 1500 mg administered IV over 
approximately 60 minutes on Day 1 of each cycle 
Chemotherapeutic agents will be administered as an IV infusion according to prescribing 
information or treatment guidance in general use by the Investigating site: 
• 
Cisplatin 70 mg/m2 IV on Day 1 of each cycle 
• 
Gemcitabine 1,000 mg/m2 IV on Day 1 of each cycle 
Day 8 of each 21-day cycle.  The following treatment will be administered as an IV infusion: 
• 
Gemcitabine 1,000 mg/m2 IV on Day 8 of each cycle 
Additionally, the following supportive care will be administered as needed: 
• 
Pegfilgrastim 6 mg SC per institutional SOC 
(alternative to Pegfilgrastim:  Filgrastim 5 µg/kg as SC/IV per institutional 
SOC) 
IMPORTANT CLINICAL NOTE:  
Durvalumab dose for Cis-Gem (& Carbo-Gem)   
*DIFFERS*  from DD MVAC 

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• Carbo-Gem Cohort:  Durvalumab plus Carboplatin + Gemcitabine  
 
Treatment with Durvalumab plus Carbo-Gem is on a 21-day cycle as described 
below: 
Day 1 of each 21-day cycle, the following treatments will be administered as an IV infusion: 
• 
Durvalumab at a fixed dose of 1500 mg administered IV over 
approximately 60 minutes on Day 1 of each cycle 
Chemotherapeutic agents will be administered as an IV infusion according to prescribing 
information or treatment guidance in general use by the Investigating site: 
• 
Carboplatin: AUC 5 IV on Day 1 of each cycle 
• 
Gemcitabine 1,000 mg/m2 IV on Day 1 of each cycle 
Day 8 of each 21-day cycle.  The following treatment will be administered as an IV infusion: 
• 
Gemcitabine 1,000 mg/m2 IV on Day 8 of each cycle 
Additionally, the following supportive care will be administered as needed: 
• 
Filgrastim 5 µg/kg as SC/IV per institutional SOC 
(alternative to Filgrastim:  Pegfilgrastim 6 mg as SC per institutional SOC) 
 
Observation before; during; and after 1st durvalumab infusion 
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 
during the infusion, 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. 
On the 1st infusion day, subjects will be monitored and vital signs collected/recorded prior to; 
during; and after infusion of durvalumab.  
BP and pulse will be collected from subjects before; during; and after each infusion at the 
following times (based on a 60-minute infusion): 
• 
Within 30 minutes before the beginning of the infusion  
• 
Every 30 minutes, ie, starting about halfway through planned 1-hour infusion period and 
continuing every 30 minutes until the end of the infusion.  If there are interruptions during 
infusion, the total allowed time from infusion start to completion of infusion should 
IMPORTANT CLINICAL NOTE:  
Durvalumab dose for Carbo-Gem (& Cis-Gem)  
*DIFFERS*  from DD MVAC 

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not exceed 4 hours at room temperature.  If infusion period exceeds 4 hours, see 
Section 5 Study Agent / See Dose and Route of Administration.  
• 
At the end of the infusion (at 60 minutes ± 5 minutes).  
• 
There should be a 1-hour observation period after the first infusion.  
The BP and pulse measurements should be taken more frequently if clinically indicated.  
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator.  For 
management of subjects who experience an infusion reaction, please refer to the toxicity and 
management guidelines in Section 6 Dose and Schedule Modifications.  
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, see above) and 
re-initiated at 50% of the initial rate until completion of the infusion.  If the infusion-related 
reaction is Grade 3 or higher in severity, study drug will be discontinued.   
Observation after subsequent durvalumab infusions 
For subjects with a prior ≤ Grade 2 infusion-related reaction to durvalumab, subsequent 
infusions may be administered at 50% of the initial rate.  
BP, pulse and other vital signs should be measured, collected/recorded prior to the start of the 
infusion.  Subjects should be carefully monitored and BP and other vital signs should be 
measured during and post-infusion as per institution standard and as clinically indicated.  
Post-Cycle 4 Procedures/End of Treatment 
An End of Treatment safety assessment will be obtained in person within 4 weeks ± 2 weeks of 
completion of neoadjuvant treatment, typically at the subject’s cystectomy pre-operative visit.  
After the completion of the 4 cycles of durvalumab and neoadjuvant chemotherapy, the subjects 
MUST undergo cystectomy within 6 weeks (on or before 42 days, no grace period).  Subjects 
who complete treatment but fail to undergo cystectomy will be considered inevaluable for 
endpoint analysis for that reason.  The following blood samples will be collected pre- and 
post-surgery: 
ctDNA Collection 
• 
Pre-Initiation of Neoadjuvant Treatment (Whole Exome-Tissue and Target 
Genes Plasma) 
• 
Upon completion of neoadjuvant treatment and prior to surgical cystectomy 
(typically at the pre-operative visit)  
• 
4 weeks post-cystectomy +/-2 weeks  
• 
12 weeks post-cystectomy +/-2 weeks (at the End of Study visit) 
In addition to the blood sample collection, tumor specimen testing will be as follows: 
• 
Tumor specimen for genomic sequencing post-cystectomy 
• 
Tumor specimen PD-L1 testing post-cystectomy 

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End of Study 
The End of Study visit is defined as the last planned visit within 12 weeks (+/- 2 weeks) post 
cystectomy. All required procedures may be completed within 7 days before the End of Study 
visit.  
Study Assessments 
Findings from screening medical history and physical examination will be used as baseline for 
the assessment of adverse events (AEs).  
Medical history  
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 and vital signs  
A complete physical examination will be performed on study days noted, 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, musculoskeletal (including spine and extremities), and neurological systems.  
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules.  Body weight is also recorded at each visit along with 
vital signs.  Height will be measured at screening only.  
Electrocardiograms 
At Screening, a single resting ECG will be obtained, on which QTcF must be ≤ 470 ms.  
Resting 12-lead ECGs will be recorded as clinically indicated throughout the study.  ECGs 
should be obtained after the subject has been in a supine position for 5 minutes and recorded 
while the subject remains in that position.  In case of clinically-significant ECG abnormalities, 
including a QTcF value > 470 ms;  2 additional 12-lead ECGs should be obtained over a brief 
period (eg, 30 minutes) to confirm the finding.  

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Clinical laboratory tests.  The following clinical laboratory tests will be performed.  
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 
 
Clinical Chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Magnesiuma 
Alanine aminotransferase 
Potassium 
Aspartate aminotransferase 
Sodium 
Bicarbonate 
Total bilirubinb 
Calcium  
Total protein 
Chloride 
Blood urea nitrogen  
Creatininec 
 
a  Magnesium is to be performed at baseline on Day 1 and as clinically indicated 
b Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed 
concurrently.  If total bilirubin is ≥ 2 × upper limit of normal (and no evidence of Gilbert’s syndrome) 
then fractionate into direct and indirect bilirubin.  
c Creatinine clearance will be calculated by data management using Cockcroft-Gault (using actual body 
weight).  
Urinalysis Tests a 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Color and appearance 
a Microscopy should be used as appropriate to investigate white blood cells and use the 
high-power field for red blood cells 
Samples for Biomarker Studies 
Blood samples will be collected for correlative studies (see Section 8) at the following 
timepoints. 
• 
Pre-initiation of neoadjuvant treatment 

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• 
Upon completion of study treatment and prior to surgical removal of bladder 
(cystectomy). 
• 
4 weeks subsequent to cystectomy.  
• 
12 weeks subsequent to cystectomy.  
Plasma sample requirements: 
A total of minimum 4 mL plasma is required to be submitted per participant per time point.  
Sample can be batch shipped frozen to Natera.  
Tissue Requirements:  
Tissue samples may be formalin-fixed, paraffin embedded (FFPE) from primary cancer 
diagnosis.  The tumor content of tissue biopsy shall not be lower than 30%.  
Below are the tissue specifications.  Natera will conduct a quality assessment of samples to 
determine if the tissue qualifies for WES.  Unqualified samples will be sent back to the 
Institution.  
Sample types for resected tissue: 
• 
Tissue block and 1 H&E slide is preferred, OR  
• 
10 unstained slides and 1 H&E slide OR  
• 
Tissue block punches and 1 H&E slides, OR  
• 
4 to 6 cores and 1 H&E slides 
Sample size (for slides): 
• 
Surface area of 9 mm2 is the minimum and 25 mm2 is ideal  
• 
5-micron thickness is the minimum and 10-micron thickness is preferred  
• 
Unbaked  
• 
For unstained slides: microdissection will be performed to select tumor rich regions and 
exclude normal tissue, necrotic areas, and lymphocytes that may decrease the tumor 
DNA content.  To assist in microdissection, site is requester to prepare a minimum of 
10 unstained slides by using the H&E to trace tumor regions on adjacent unstained 
slides.  
PD-L1 testing 
To ensure comparability of data across all studies of durvalumab and to gain real world 
experience on the performance of this assay, this study will include PD-L1 testing utilize the 
Ventana SP263 assay.  Testing will be performed at the Stanford Healthcare Clinical 
Laboratory.  
Sample collection for PD-L1 testing 
• 
The preferred tumor sample for the determination of a subject’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy.  Samples taken at 

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this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant.  
• 
Samples should be collected via tumor biopsy.  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 
 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated samples, the samples that have not been 
processed will be disposed of or destroyed, and the action documented.  As collection of the 
biological samples is an integral part of the study, the subject is withdrawn from further study 
participation. 
The Principal Investigator will ensure that biological samples from that subject, if stored at the 
study site, are immediately identified, disposed of /destroyed, and the action documented and 
will ensure the laboratory(ies) holding the samples is/are informed about the withdrawn consent 
immediately and that samples are disposed/destroyed, the action documented.  Additionally, the 
study team will ensure that the subject is informed about the sample disposal. 
 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary 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, correction of metabolic 
disorders, optimal symptom control, and pain 
management  
Should be used, when necessary, for all 
subjects 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 

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Prohibited Concomitant Medications 
Prohibited medication/ 
class of drug: 
 
Usage: 
Any investigational anticancer 
therapy other than those under 
investigation in this study 
Should not be given concomitantly whilst the subject is 
on study treatment 
mAbs against CTLA-4, PD-1, or 
PD-L1 other than those under 
investigation in this study 
Should not be given concomitantly whilst the subject is 
on study treatment 
Any concurrent chemotherapy, 
radiotherapy, immunotherapy, or 
biologic or hormonal therapy for 
cancer treatment other than those 
under investigation in this study 
Should not be given concomitantly whilst the subject is 
on study treatment.  (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable.  
Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by local 
surgery or radiotherapy]) 
Immunosuppressive medications 
including, but not limited to, 
systemic corticosteroids at doses 
exceeding 10 mg/day for > 3 days,  
methotrexate, azathioprine, and 
tumor necrosis factor-α blockers 
Should not be given concomitantly,  or used for 
premedication prior to the infusions.  The following are 
allowed exceptions: 
• Use of immunosuppressive medications for the 
management of IP-related AEs,  
• Short-term premedication for subjects receiving 
combination cisplatin agent where the prescribing 
information for the agent requires the use of steroids 
for documented hypersensitivity reaction and nausea 
is allowed 
• Use in subjects with contrast allergies.  
• In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted.  
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related events 
experienced by the subject (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc) or as 
anti-nausea premedication for cisplatin chemotherapy 
Drugs with laxative properties and 
herbal or natural remedies for 
constipation 
Should be used with caution during the study 
4.2 
Criteria for Removal from Study 
Permanent discontinuation of study 

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An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question: 
1. An individual subject will not receive any further durvalumab monotherapy if their weight 
falls to 30 kg or less 
2. Withdrawal of consent or lost to follow-up 
3. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing 
4. 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 
5. A radical cystectomy procedure is not performed (ie, a partial cystectomy or no 
cystectomy is performed) 
6. Pregnancy or intent to become pregnant 
7. Any AE that meets criteria for discontinuation  
8. Grade ≥ 3 infusion reaction 
9. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; eg, refusal to adhere to scheduled visits 
10. Initiation of alternative anticancer therapy including another investigational agent 
11. Confirmation of PD and investigator determination that the subject is no longer benefiting 
from treatment with durvalumab  
Withdrawal of consent 
Subjects are free to withdraw from the study at any time (treatment with durvalumab and 
assessments) without prejudice to further treatment. 
Subjects who withdraw consent for further participation in the study will not receive any further 
durvalumab or further study observation.  Note that the subject may be offered additional tests 
or tapering of treatment to withdraw safely. 
A subject who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE.  The Investigator will follow up AEs outside of the clinical study.  
An individual subject will not receive any further treatment with durvalumab if any of the 
following occur in the subject in question: 
• 
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing 
• 
Pregnancy or intent to become pregnant 
• 
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with durvalumab (eg, refusal to adhere 
to scheduled visits) 

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• 
Initiation of alternative anticancer therapy including another investigational agent 
• 
Clinical progression, ie, Investigator determination that the subject is no longer benefiting 
from treatment with durvalumab, with or without radiological progression. 
Any AE that meets criteria for discontinuation as defined in the Dosing Modification and Toxicity 
Management Guidelines (Appendix 1) 
If a subject withdraws consent, they will be specifically asked if they are withdrawing consent to:  
• 
All further participation in the study including any further follow up  
• 
Withdrawal of consent to the use of their study generated data 
• 
Withdrawal to the use of any samples 
4.3 
Alternatives 
Subjects may choose not to participate in the trial and get standard of care treatment with either 
chemotherapy followed by surgery or surgery alone as determined by the treating physician.  
5. 
STUDY AGENT INFORMATION 
5.1 
Study Agent 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab to the investigator as a 500-mg vial solution for infusion after dilution. 
Formulation; Packaging; and 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 dehydrate;  and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 
6.0.  The nominal fill volume is 10.0 mL.  Investigational product vials are stored at 2°C to 8°C 
(36°F to 46°F) and must not be frozen.  Drug product should be kept in secondary packaging 
until use to prevent excessive light exposure 
Subjects receiving durvalumab will receive 1500 mg once every 3 weeks or 750 mg once every 
2 weeks durvalumab, via IV.  
Dosing and Administration:  
The investigational agent durvalumab at will be administered by IV infusion at fixed doses of 
750 mg (DD MVAC cohort) or 1500 mg (Cis-Gem or Carbo-Gem cohorts), in combination with 
the investigator’s choice of 3 standard therapeutic regimens.  The selection is offered for 
investigator discretion based on renal function.  If creatine clearance is > 50 cc, the investigator 
may choose between DD MVAC or Gemcitabine + Cisplatin.  If Cr clearance is less than 50 cc 
then the Carboplatin + Gemcitabine (Carbo-Gem) regimen may be given.  
The therapeutic regimens are described in detail at Section 4 Treatment Plan / Treatment 
Administration per Cycle.  
Allowable Infusion Period and Need for Fresh Preparations of Durvalumab  
The target infusion period is 1-hour, but can be extended as needed due to interruptions for 
up to 4 hours total.  In the event that the infusion exceeds 4 hours, the infusion should be 
terminated.  Record the amount not infused, and dispose of the durvalumab per protocol.  

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Obtain a fresh preparation of durvalumab from the Stanford Investigational Drug Service (IDS, 
the investigational pharmacy) for the amount not infused, and re-initiate the infusion with 
freshly-prepared durvalumab.  
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator.  
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 management of subjects who experience an infusion reaction, please refer to the toxicity 
and management guidelines in  
For any subjects that experienced a prior ≤ Grade 2 infusion-related reaction to durvalumab, 
subsequent infusions may be administered at 50% of the initial rate.  If a infusion-related 
reaction is Grade 3 or higher in severity, study drug will be discontinued for that subject.   
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. 
Observation after subsequent durvalumab infusions 
On the 1st infusion day, subjects will be monitored and vital signs collected/recorded prior to;  
during;  and after infusion of durvalumab (1 hour or as clinically indicated).  Subsequent 
observation will be according to institutional standard.  
Preparation of durvalumab for administration with an IV bag 
The dose of durvalumab for administration will be prepared by the IDS 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 
Infusion solution must be allowed to equilibrate to room temperature prior to commencement of 
administration.  
A dose of 750 mg (DD MVAC cohort) or 1500 mg (Cis-Gem or Carbo-Gem cohorts) will be 
administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final 
durvalumab concentration ranging from 1 to 15 mg/mL, and delivered through an IV 
administration set with a 0.2- or 0.22-μm in-line filter.  Add 30.0 mL of durvalumab (ie, 1500 mg 
of durvalumab) to the IV bag.  The IV bag size should be selected such that the final 
concentration is within 1 to 15 mg/mL.  Mix the bag by gently inverting to ensure homogeneity of 
the dose in the bag. 
The standard infusion time is 1 hour.  In the event that there are interruptions during infusion, 
the total allowed infusion time should not exceed 4 hours at room temperature.  If either the 
preparation time or projected infusion time exceeds 4 hours, a new dose must be prepared from 

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new vials.  Durvalumab does not contain preservatives, and any unused portion must be 
discarded.  
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion 
set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered and document if the line 
was not flushed. 
Accountability and dispensation 
Drug accountability records will be kept during the study by the IDS.  The IDS will account for all 
investigational study drug dispensed, and also for appropriate destruction.  Certificates of 
delivery and destruction must be signed. 
6. 
DOSE AND SCHEDULE MODIFICATIONS 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab.  
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. 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the initial 
rate until completion of the infusion.  If the infusion-related reaction is Grade 3 or higher in 
severity, study drug will be discontinued.   
Subjects should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis.  In the absence of a clear alternative etiology, events should be considered 
potentially immune related. 
Following the first dose of IP, subsequent administration of durvalumab can be modified based 
on toxicities observed as described in the Dosing Modification and Toxicity Management 
Guidelines.  These guidelines have been prepared to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities.  These guidelines apply to AEs 
considered causally related to durvalumab monotherapy. 
6.1.  Dose Modifications for Durvalumab  
Dose reductions on durvalumab are not permitted.  
Subjects should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis.  In the absence of a clear alternative etiology, events should be considered 
potentially immune related. 

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All toxicities will be graded according to NCI Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.  
6.2.  Dose Modifications for Gemcitabine and Cisplatin (Cis-Gem) 
6.2.1.  Hematologic Toxicity 
Day 1 
For ANC < 1,000 on Day 1, delay treatment until the ANC is > 1000.  If delay is 1 week or less, 
continue at the same dose and consider pegfilgrastim with subsequent cycles, if not receiving.  
If the delay is for more than a week and pegfilgrastim has not been used, include pegfilgrastim 
in all subsequent cycles.  If there is a dose delay of more than 1 week due to neutropenia 
despite pegfilgrastim use, reduce cisplatin and gemcitabine by one dose level for this and all 
subsequent cycles and continue pegfilgrastim. 
For platelets < 100,000 on Day 1, delay treatment until platelets are > 100,000.  If the delay is 
1 week or less, continue at the same dose levels.  If the delay is for more than a week, reduce 
the gemcitabine by one dose level for this and all subsequent cycles. 
Day 8 
For and ANC < 500, hold gemcitabine and reduce both cisplatin and gemcitabine by one dose 
level for all subsequent cycles. 
For platelets < 50,000, hold gemcitabine and reduce gemcitabine by one does level for all 
subsequent cycles. 
6.2.2.  Febrile Neutropenia 
Febrile neutropenia is defined as ANC of < 500 and a temperature of 38.3°C orally (101° °C 
(100.4°F) for more than 1 hour.  Add pegfilgrastim if not previously included, continuing at the 
same dose level.  If pegfilgrastim had been utilized, then dose reduce both the gemcitabine and 
cisplatin by one dose level for all subsequent cycles and continue pegfilgrastim. 
6.2.3.  Kidney Dysfunction 
Calculate the CrCl on Day 1 of each cycle.  If CrCl is < 50 mL/min, hold cisplatin for 
up to 1 week.  If Cr cl does not improve to > 50 mL/min in 1 week despite hydration and other 
supportive measures discontinue the chemotherapy and proceed to surgery.  If the CrCl 
improves to > 50cc proceed with split dose cisplatin administration on Days 1 and 8.  If Cr Cl 
improves to > 60cc on day 1 of subsequent cycle, then split dose not required 
If the CrCl is between 50 to 60 mL/min on Day 1 of chemotherapy, administer cisplatin in split 
dosing, without a dose level reduction.  Pegfilgrastim or filgrastim will be given on Day 9 or 
Days 9 to 13, respectively, when the cisplatin dose is split.  With split dosing, if CrCl is 
< 50 mL/min on Day 8,the cisplatin is to be held for that day. 
6.2.4.  Liver Dysfunction 
For a total bilirubin of > 1.5 × the upper limit of normal (or 3 × ULN in subjects with Gilbert’s 
syndrome), hold therapy until the bilirubin is < 1.6 × ULN (or < 3 × ULN in those with Gilbert’s 
syndrome), and then restart with a one dose level reduction in gemcitabine for this and all 
remaining cycles. 

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6.2.5.  Neurologic Toxicity 
For Grade 3 neuropathy, hold chemotherapy until this resolve to Grade 1 or 2 and then resume 
with a one dose level reduction in the cisplatin.  For Grade 4 neuropathy, remove the subject 
from protocol treatment. 
6.2.6.  Gastrointestinal Toxicity 
For Grade 3 or 4 vomiting, despite maximal antiemetic medical intervention with aprepitant, 
corticosteroids, and 5HT-3 antagonists (eg, ondansetron), proceed with a dose reduction for the 
next cycle in both cisplatin and gemcitabine.  If Grade 3 or 4 vomiting occurs despite one dose 
reduction in chemotherapy and maximal antiemetic therapy, remove the subject from protocol 
treatment. 
6.2.7.  Other toxicities 
For all other, non-specified adverse events at Grade 2, subjects should be treated 
symptomatically.  For all other Grade 3 or 4 toxicities (excluding alopecia and skin pigment 
changes), hold cisplatin and gemcitabine and monitor the subject at least weekly.  If toxicity 
resolves to Grade 1 by 1 dose level for this and all subsequent cycles.  Any single delay in 
chemotherapy of more than 3 weeks or cumulative delays of more than 4 weeks will lead to 
removal from protocol treatment and referral to surgery. 
6.3.  Dose Modifications for Carboplatin and Gemcitabine (Carbo-Gem) 
6.3.1.  Hematologic Toxicity 
Day 1:   
For ANC < 1,000 on Day 1, delay treatment until the ANC is > 1000.  If delay is 1 week or less, 
continue at the same dose and consider pegfilgrastim with subsequent cycles, if not receiving.  
If the delay is for more than a week and pegfilgrastim has not been used, include pegfilgrastim 
in all subsequent cycles.  If there is a dose delay of more than 1 week due to neutropenia 
despite pegfilgrastim use, reduce cisplatin and gemcitabine by one dose level for this and all 
subsequent cycles and continue pegfilgrastim. 
For platelets < 100,000 on Day 1, delay treatment until platelets are > 100,000.  If the delay is 
1 week or less, continue at the same dose levels.  If the delay is for more than a week, reduce 
the gemcitabine by one dose level for this and all subsequent cycles. 
Day 8:   
For and ANC < 500, hold gemcitabine and reduce both cisplatin and gemcitabine by one dose 
level for all subsequent cycles. 
For platelets < 50,000, hold gemcitabine and reduce gemcitabine by one does level for all 
subsequent cycles. 
6.3.2.  Febrile Neutropenia 
Febrile neutropenia is defined as ANC of < 500 and a temperature of 38.3°C orally (101° °C 
(100.4°F) for more than1 hour.  Add pegfilgrastim if not previously included, continuing at the 
same dose level.  If pegfilgrastim had been utilized, then dose reduce both the gemcitabine and 
cisplatin by one dose level for all subsequent cycles and continue pegfilgrastim. 

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6.3.4.  Liver Dysfunction 
For a total bilirubin of > 1.5 × the upper limit of normal (or 3 × ULN in subjects with Gilbert’s 
syndrome), hold therapy until the bilirubin is < 1.6 × ULN (or < 3 × ULN in those with Gilbert’s 
syndrome), and then restart with a one dose level reduction in gemcitabine for this and all 
remaining cycles. 
6.3.5.  Neurologic Toxicity 
For Grade 3 neuropathy, hold chemotherapy until this resolve to Grade 1 or 2 and then resume 
with a one dose level reduction in the carboplatin.  For Grade 4 neuropathy, remove the subject 
from protocol treatment. 
6.3.6.  Gastrointestinal Toxicity 
For Grade 3 or 4 vomiting, despite maximal antiemetic medical intervention with aprepitant, 
corticosteroids, and 5HT-3 antagonists (eg, ondansetron), proceed with a dose reduction for the 
next cycle in both carboplatin and gemcitabine.  If Grade 3 or 4 vomiting occurs despite one 
dose reduction in chemotherapy and maximal antiemetic therapy, remove the subject from 
protocol treatment. 
6.3.7.  Other toxicities 
For all other, non-specified adverse events at Grade 2, subjects should be treated 
symptomatically.  For all other Grade 3 or 4 toxicities (excluding alopecia and skin pigment 
changes), hold carboplatin and gemcitabine and monitor the subject at least weekly.  If toxicity 
resolves to Grade 1 by 1 dose level for this and all subsequent cycles.  Any single delay in 
chemotherapy of more than 3 weeks or cumulative delays of more than 4 weeks will lead to 
removal from protocol treatment and referral to surgery. 
6.4.  Dose-dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin 
(DD MVAC) 
6.4.1.  Hematologic Toxicity 
For ANC < 1000 or platelets < 100,000 on Day 1, delay treatment until the ANC is > 1000 and 
platelets > 100,000.  If delay is 1 week or less, continue at the same doses.  If the delay is for 
more than a week, reduce methotrexate, vinblastine, doxorubicin, and cisplatin by one dose 
level for this and all subsequent cycles. 
For febrile neutropenia, defined as ANC of < 500 and a temperature of 38.3 C orally (101 F) 
dose reduce all chemotherapy agents by one dose level and consider switching to pegfilgrastim 
(if previously giving filgrastim). 
6.4.2.  Kidney Dysfunction 
Calculate the CrCl on Day 1 of each cycle.  If CrCl is < 50 mL/min, hold chemotherapy for up to 
1 week.  If Cr cl does not improve to > 50mL/min in 1 week despite hydration and other 
supportive measures discontinue the chemotherapy and proceed to surgery.  If the CrCl 
improves to > 50cc proceed with split dose cisplatin administration on Days 1 and 8.  If Cr Cl 
improves to > 60cc on day 1 of subsequent cycle, then split dose not required 
If the CrCl is between 50 to 60 mL/min on Day 1 of chemotherapy, administer cisplatin in split 
dosing, without a dose level reduction.  Pegfilgrastim or filgrastim will be given on Day 9 or 

Amendment 5  IRB-48062 
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Days 9 to 13, respectively, when the cisplatin dose is split.  With split dosing, if CrCl is 
< 50 mL/min on Day 8,the cisplatin is to be held for that day. 
6.4.3.  Liver Dysfunction 
For a total bilirubin of > 1.5 × the upper limit of normal (or 3 × ULN in subjects with Gilbert’s 
syndrome), hold therapy until the bilirubin is < 1.6 × ULN (or < 3 × ULN in those with Gilbert’s 
syndrome), and then restart with a one dose level reduction in doxorubicin and vinblastine for 
this and all remaining cycles. 
6.4.4.  Neurologic Toxicity 
For Grade 3 neuropathy, hold chemotherapy until this resolve to Grade 1 or 2 and then resume 
with a one dose level reduction in the cisplatin and vinblastine.  For Grade 4 neuropathy, 
remove the subject from protocol treatment. 
6.4.5.  Gastrointestinal Toxicity 
For Grade 3 or 4 vomiting, despite maximal antiemetic medical intervention with aprepitant, 
corticosteroids, and 5HT-3 antagonists (eg, ondansetron), proceed with a dose reduction for the 
next cycle in both, methotrexate and doxorubicin.  If Grade 3 or 4 vomiting occurs despite one 
dose reduction in chemotherapy and maximal antiemetic therapy, remove the subject from 
protocol treatment. 
6.4.6.  Stomatitis 
For Grade 2 toxicity, delay infusion until it resolves to Grade 0 or 1.  For Grade 3 or 4 toxicity, 
delay chemotherapy until it resolves to Grade 0 or 1 and reduce doxorubicin, vinblastine and 
methotrexate by one dose level on all subsequent cycles. 
6.4.7.  Other Toxicities 
For all other, non-specified adverse events at Grade 2, they should be treated symptomatically, 
as indicated.  For all other Grade 3 or 4, hold all chemotherapy and monitor the subject at least 
weekly.  If toxicity resolves vinblastine, doxorubicin, and cisplatin by one dose level for this and 
all subsequent cycles.  Any single delay in chemotherapy of more than 3 weeks or cumulative 
delays of more than 4 weeks will lead to removal from protocol treatment and referral to surgery. 
6.5.  Filgrastim (G-CSF) Dose Modifications 
Dose adjustments for toxicities associated with filgrastim (G-CSF) (bone pain, splenomegaly, 
abnormalities in uric acid concentrations, LDH and alkaline phosphatase, transient elevations of 
serum creatinine and aminotransferase activity) Dose modifications for G-CSF toxicity should 
only be initiated if symptomatic control of the toxicity fails (ie, analgesics such as 
acetaminophen or acetaminophen with codeine for myalgias or bone pandect.). 
Toxicity Grade  
Dose Adjustment 
Grade 0 to 1:   
No change 
Grade 2:   
Decrease filgrastim to 3 µg/kg/day 
Grade 3 to 4:   
Discontinue filgrastim 

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Cisplatin Dose Level 
 
Cr Cl > 59 
Cr Cl > 50< 60 
0 
70 mg/m2 
35 mg/m2 Days 1 and 8 for 
Cis/Gem; and Days 1 and 2 
for DD MVAC 
-1 
50 mg/m2 
25 mg/m2 Days 1 and 8 for 
Cis/Gem; and Days 1 and 2 
for DD MVAC 
Gemcitabine Dose Level 
Level 0 
1000 mg/m2 
Level -1 
750 mg/m2 
Level -2 
500 mg/m2 
Methotrexate Dose Level 
Level 0 
30 mg/m2 
Level -1 
23 mg/m2 
Level -2 
15 mg/m2 
Vinblastine Dose Level 
Level 0 
3 mg/m2 
Level -1 
2.3 mg/m2 
Level -2 
1.5 mg/m2 
Doxorubicin Dose Level 
Level 0 
30 mg/m2 
Level -1 
23 mg/m2 
Level -2 
15 mg/m2 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related, including new or aggravated clinically-relevant 

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abnormal medical findings at physical examination.  An adverse event can be any unfavorable 
and unintended sign or symptom, including abnormal laboratory findings, or disease, that is 
temporally associated with the use of a drug, and does not imply any judgment about causality.  
This also includes events of clinical deterioration such as tumor relapse, recurrence, or 
upstaging, or new cancers.  An adverse reaction is any event that is caused by a drug or device, 
ie, possibly-, probably-, or definitely-related to the use of the drug or device.  
7.1 
Potential Adverse Events 
Adverse events are described in the FDA-approved prescribing information for 
durvalumab (Imfinzi).  
7.2 
Adverse Event Reporting 
AEs and SAEs will be collected from the time of the subject signing the informed consent form 
until the follow-up period is completed (90 days after the last dose of durvalumab).  If an event 
that starts post the defined safety follow up period noted above is considered to be due to a late 
onset toxicity to study drug then it should be reported as an AE or SAE as applicable.  
During the course of the study, all AEs and SAEs should be proactively followed up for each 
subject for as long as the event is ongoing.  Every effort should be made to obtain a resolution 
for all events, even if the events continue after the subject has discontinued study drug or the 
study has completed.  
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.  AstraZeneca 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. 
The following variables will be collected for each AE: 
In addition, the following variables will be collected for SAEs as applicable: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
The maximum CTCAE grade reported 
• 
Changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IPs (yes or no) 
• 
Action taken with regard to IPs 
• 
Administration of treatment for the AE 
• 
Outcome 
• 
In addition, the following variables will be collected for SAEs: 
• 
Date the AE met criteria for SAE 
• 
Date the Investigator became aware of the SAE 
• 
Seriousness criteria fulfilled 

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• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether an autopsy was performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment in relation to other medication 
Description of the SAE 
The grading scales found in the revised NCI CTCAE version 5 will be utilized for all events with 
an assigned CTCAE grading.  For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used.  A copy of the CTCAE v5 can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov).  
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 subject 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. 
Causality collection 
The Investigator will assess causal relationship between the IPs and each AE and answer “yes” 
or “no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?” 
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship is 
implied as “yes.” 
Relationship to protocol procedures 
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment–emergent 

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(ie, SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (eg, blood collection).  The following guidelines should be used by Investigators to assess 
the relationship of SAEs to the protocol: 
• 
Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the subject’s 
medical record. 
• 
Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol.  The alternative etiology must be 
documented in the study subject’s medical record. 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit/you were 
last asked?” or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred, when possible, to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
Adverse events based on examinations and tests 
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarize.  If deterioration in a laboratory value or vital sign is associated with clinical signs 
and symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result or vital sign will be considered as additional information.  Whenever possible, the clinical 
rather than the laboratory term (eg, anemia vs low hemoglobin value) should be used.  In the 
absence of clinical signs or symptoms, clinically-relevant deteriorations in non-mandated 
parameters should be reported as AEs. 
Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need to 
be reported as SAEs.   
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the IP 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 
or progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE.  Events that are unequivocally due to disease progression 
should not be reported as an AE during the study. 
New cancers 
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the IP and have been identified 
after the subject’s inclusion in this study. 

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Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined follow-up 
period after the administration of the last dose of study drug, must be reported as follows: 
• 
Death clearly resulting from disease progression, or for any unknown cause, should be 
documented accordingly.  
• 
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the AstraZeneca Patient Safety as an SAE 
within 24 hours. The report should contain a comment regarding the co-involvement of 
progressive disease, if appropriate, and should assign main and contributory causes of 
death. 
• 
Within 24 hours after the Principal Investigator is notified, of a SAE, each such SAE will 
be reported by Stanford secure email to 
, using a 
study-specific CRF or the Stanford Cancer Institute CRF for SAE reporting.  In the email, 
indicate the OnCore or eProtocol number in the subject line.  CCTO-Safety will post the 
report to the OnCore study record, where it will be available for review by the Stanford 
Data Safety and Monitoring Committee (DSMC).  
• 
In the event of death due to an unknown cause, a post-mortem may be helpful in the 
assessment of the cause of death.  If performed, a copy of the post-mortem results 
should be forwarded to AstraZeneca Patient Safety or its representative within the usual 
timeframes. 
• 
If a death occurs as a result of an event that started after the defined safety follow-up 
period, and is considered to be due to a late-onset toxicity to study drug, then it should 
also be reported as an SAE. 
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. 
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 subjects 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. 

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Reporting of serious adverse events 
All SAEs, whether or not considered causally related to durvalumab, or to the study 
procedure(s), will be reported to AstraZeneca, as well as the IRB of record according to local 
requirements.  Notifications to AstraZeneca will use a MedWatch/AdEERs form or equivalent.  
The reporting period for SAEs is the period immediately following the time that written informed 
consent is obtained through 90 days after the last dose of durvalumab or until the initiation of 
alternative anticancer therapy.  The investigator is responsible for informing the IRB of record 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 
21CFR§312.32, and will concurrently forward all such reports to AstraZeneca.  A copy of the 
MedWatch/AdEERs report must be emailed to AstraZeneca at the time the event is reported to 
the FDA.  It is the responsibility of the sponsor to compile all necessary information and ensure 
that the FDA receives a report according to the FDA reporting requirement timelines and to 
ensure that these reports are also submitted to AstraZeneca at the same time. 
A cover page should accompany the MedWatch/AdEERs notification to AstraZeneca indicating 
the following: 
• 
“Notification from an Investigator-sponsored Study” 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-##-#####) 
The Investigator 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: 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA. 
Reporting of deaths to AstraZeneca 
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 to AstraZeneca as follows: 
Death that is clearly the result of disease progression should be documented but should not be 
reported as an SAE. 
Where death is not due (or not clearly due) to progression of the disease under study, the AE 
causing the death must be reported to AstraZeneca as a SAE within 24 hours.  The report 
should contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death.  
Deaths with an unknown cause should always be reported as a SAE.  
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented but will not be reported as an SAE.  However, if an 
investigator learns of any SAEs, including death, at any time after the subject has been 

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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. 
Other events requiring reporting 
Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified 
in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox.  If 
the overdose results in an AE, the AE must also be recorded as an AE ).  Overdose does not 
automatically make an AE serious, but if the consequences of the overdose are serious, for 
example death or hospitalization, the event is serious and must be recorded and reported as an 
SAE.  There is currently no specific treatment in the event of an overdose of durvalumab.  
The investigator will use clinical judgment to treat any overdose. 
Hepatic function abnormality 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case in a 
study subject, with or without associated clinical manifestations, is required to be reported as 
“hepatic function abnormal” within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca Patient Safety using the designated Safety e-mailbox, unless a definitive underlying 
diagnosis for the abnormality (eg, cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed.  The criteria for a potential Hy’s Law case is 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 × Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP). 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject 
will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately.  Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
Pregnancy 
Maternal exposure 
Female subjects will be advised to use a medically-acceptable method of birth control for 
90 days after the last dose of durvalumab.  If a subject becomes pregnant during the course of 
the study, durvalumab should be discontinued immediately.  

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Pregnancy itself is not regarded as an AE unless there is a suspicion that durvalumab 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 subject 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.  
Paternal exposure  
Male subjects will be advised to use a medically-acceptable method of birth control, and should 
refrain from fathering a child or donating sperm during the study and for 180 days after the last 
dose of durvalumab.  
Pregnancy of the subject’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 180 days after the last 
dose of durvalumab + any drug combination therapy or 90 days after the last dose of 
durvalumab monotherapy, whichever is the longer time period 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 subject’s partner.  Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the relevant 
Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.  
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the subject or 
has the potential to cause harm to the subject.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject. 
Medication error includes situations where an error  
• 
Occurred 
• 
Was identified and intercepted before the subject received the drug 
• 
Did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 

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• 
Drug name confusion 
• 
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed, eg, kept in the fridge when it should be at room 
temperature  
• 
Wrong subject received the medication  
• 
Wrong drug administered to subject  
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Subject accidentally missed drug dose(s), eg, missed appointment  
• 
Accidental overdose (will be captured as an overdose) 
• 
Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs 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 works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated with 
the medication error and within 30 days for all other medication errors.  
Adverse events will be graded according to CTCAE v5.  Both Serious and Non-Serious Adverse 
Events will be clearly noted in source documentation and listed on study specific Case Report 
Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse Event (AE) to 
determine whether it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation.  All Serious Adverse Events (SAEs) will 
be tracked until resolution, or until 30 days after the last dose of the study treatment.  
SAEs (per 21CFR§312.32) and all subsequent follow-up reports will be reported to the Stanford 
Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study-specific CRF 
regardless of the event’s relatedness to the investigation.  
8. 
CORRELATIVE/SPECIAL STUDIES  
Samples to be collected are defined in Section 4.  
• 
Whole blood or frozen plasma 
• 
Buffy coat (or other germline DNA) 

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Blood for ctDNA will be drawn at baseline, post-chemotherapy,  
post-cystectomy at 4 weeks and at 12 weeks 
Time Point 
Time 
Test-Sample 
1 
Pre-Initiation of Neoadjuvant Treatment 
Whole Exome-Tissue 
1 
Pre-Initiation of Neoadjuvant Treatment 
Target Genes 
[16]-Plasma 
2 
Upon Completion of Study Treatment /  
Prior to Surgical Removal of Bladder  
Target Genes 
[16]-Plasma 
3 
4 weeks Post-surgical Removal of Bladder 
Target Genes 
[16]-Plasma 
4 
12 weeks Post-surgical Removal of Bladder 
Target Genes 
[16]-Plasma 
Natera will provide WES and 4 plasma test time points [1 Signatera test] per study participant .  
Natera will design custom two-side SNV assays based on SNV’s identified in the whole exome 
sequencing data generated from the tumor tissue.  Natera will extract ctDNA from plasma, the 
ctDNA will be used to prepare Natera libraries.  The ctDNA libraries will be analyzed using 
Natera’s custom SNV assays.  The ctDNA will be analyzed according to Natera’s protocol and 
SNV calling pipeline.  
Natera ctDNA Analysis 
Detection and monitoring of tumor-specific mutations in cell-free DNA has great potential to 
improve patient care by detecting cancer early, assisting adjuvant therapy decision-making, 
determining treatment effects and assessing the need for follow-up intervention.  Existing 
methodologies for recurrence monitoring (eg, protein biomarkers, CT imaging) have limitations, 
which may include increased health risk or discomfort for the patient, lower sensitivity and 
specificity, and/or higher costs.  
Natera, Inc., (NASDAQ: NTRA), a leader in non-invasive genetic testing, develops and 
commercializes non-invasive methods for analyzing circulating free DNA (cfDNA) in plasma.  
The mission of the company is to transform the diagnosis and management of genetic disease.  
In pursuit of that mission, Natera operates a CAP-accredited laboratory certified under the 
Clinical Laboratory Improvement Amendments (CLIA) in San Carlos, CA, and it currently offers 
a host of proprietary genetic testing services primarily to OB/GYN physicians and fertility 
centers, as well as to genetic laboratories through its cloud-based Constellation™ software 
system. 
Leveraging its unique capabilities in detection of cfDNA, Natera is also applying its proprietary 
technology for improved treatment of cancer through early detection and recurrence monitoring.  
Natera aims to create pre-designed or personalized liquid biopsy assays through detection of 
copy number variants and single nucleotide changes.  A recent publication in Nature illustrates 
Natera’s proprietary technology that detected mutations in cfDNA for both clonal and subclonal 
mutations in early-stage lung cancer patients as part of the TRACERx study.  This publication 
illustrates how Natera’s assay identified recurrence 70 days [+/-] before it was identified in a 
routine clinical setting (Abbosh, et al,, 2017, Nature, 545:446).  

Amendment 5  IRB-48062 
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PD-L1 testing 
The Ventana SP263 assay to measure PD-L1 in tumors 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.  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. 

Amendment 5  IRB-48062 
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31 JAN 2020 
9. 
STUDY CALENDAR BY COHORT (all receive durvalumab) 
 
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin cohort (“DD MVAC” 14-day Cycle) 
Procedure 
Screeninga Cycle 1 
Day 1c 
Cycle 1 
Day 2c 
Cycle 2 
Day 1 c 
Cycle 2 
Day 2 c 
Cycle 3 
Day 1 c 
Cycle 3 
Day 2 c 
Cycle 4 
Day 1 c 
Cycle 4 
Day 2 c 
EOT 
Safety 
Visit 
Surgery 
ctDNA 
Collection  
End of 
Study Visit 
Scheduling Window (Days) 
-30 to -1 
(+2) 
(+2) 
(+2) 
(+2) 
(+2) 
(+2) 
(+2) 
(+2) 
4 weeksm 
(+/- 2 
weeks) 
 
4 weeks 
post-
cystectomy 
(+/- 2 
weeks) 
12 weeks 
post-
cystectomy 
(+/- 2 
weeks) 
Informed Consenth 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Vital signs, weight, & heightd 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Complete blood count w/differential 
Xf 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Comprehensive metabolic panel 
including Mgi 
Xf 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Coagulation (PT, PTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkersk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
12-lead ECGg 
X 
 
 
 
 
 
 
 
 
 
 
 
 

Amendment 5  IRB-48062 
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31 JAN 2020 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor specimen testing  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
CT or MRI of abdomen and pelvise  
X 
 
 
 
 
 
 
 
 
X 
 
 
XL 
CT or X-ray of cheste 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan (if alk phos is elevated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event collection 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant medications  
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
TREATMENT 
Durvalumab (750mg) 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Methotrexate 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Vinblastine 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Doxorubicin 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Cisplatin  
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Cystectomyj 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 

Amendment 5  IRB-48062 
Page 54 of 66 
31 JAN 2020 
 
Cisplatin plus Gemcitabine cohort (“Cis-Gem,” 21-day cycle) 
Procedure 
Screeninga Cycle 1 
Day 1 b 
Cycle 1 
Day 8 
Cycle 2 
Day 1 b 
Cycle 2 
Day 8 
Cycle 3 
Day 1 b 
Cycle 3 
Day 8 
Cycle 4 
Day 1 b 
Cycle 4 
Day 8 
EOT 
Safety 
Visit 
Surgery 
ctDNA 
Collection  
End of 
Study Visit 
Scheduling Window (Days) 
-30 to -1 
(+/- 2) 
(+2) 
(+/- 2) 
(+2) 
(+/- 2) 
(+2) 
(+/- 2) 
(+2) 
4 weeksm 
(+/- 2 
weeks)  
 
4 weeks 
post-
cystectomy 
(+/- 2 
weeks) 
12 weeks 
post-
cystectomy 
(+/- 2 
weeks) 
Informed Consenth 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Vital signs, weight,  & heightd 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Complete blood count w/differential 
Xf 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Comprehensive metabolic panel 
including Mgi 
Xf 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Coagulation (PT, PTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV serology   
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkersk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
12-lead ECGg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor specimen testing 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
CT or MRI of abdomen and pelvise  
X 
 
 
 
 
 
 
 
 
X 
 
 
XL 
CT or X-ray of cheste  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan (if alk phos is elevated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 

Amendment 5  IRB-48062 
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31 JAN 2020 
Adverse event collection 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant medications  
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
TREATMENT 
Durvalumab (1500mg) 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Cisplatin  
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Gemcitabine  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cystectomyj 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 

Amendment 5  IRB-48062 
Page 56 of 66 
31 JAN 2020 
 
Carboplatin plus Gemcitabine cohort (“Carbo-Gem,” 21-day cycle) 
Procedure 
Screeninga Cycle 1 
Day 1 
Cycle 1 
Day 8b 
Cycle 2 
Day 1 
Cycle 2 
Day 8b 
Cycle 3 
Day 1 
Cycle 3 
Day 8b 
Cycle 4 
Day 1 
Cycle 4 
Day 8b 
EOT 
Safety 
Visit 
Surgery 
ctDNA 
Collection  
End of Study 
Visit 
Scheduling Window (Days) 
-30 to -1 
(+/- 2) 
(+2) 
(+/- 2) 
(+2) 
(+/- 2) 
(+2) 
(+/- 2) 
(+2) 
4 
weeksm 
(+/- 2 
weeks) 
 
4 weeks 
post-
cystectomy 
(+/- 2 weeks) 
12 weeks 
post-
cystectomy 
(+/- 2 weeks) 
Informed Consenth 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Vital signs, weight, & heightd 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Complete blood count 
w/differential 
Xf 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Comprehensive metabolic panel 
including Magnesiumi 
Xf 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Coagulation (PT, PTT, INR)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BiomarkersK 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
12-lead ECGg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor specimen testing  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
CT or MRI of abdomen and pelvise  
X 
 
 
 
 
 
 
 
 
X 
 
 
XL 
CT or X-ray of cheste 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan (if alk phos is elevated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 

Amendment 5  IRB-48062 
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31 JAN 2020 
Adverse event collection 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant medications  
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
TREATMENT 
Durvalumab (1500mg) 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Carboplatin  
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Gemcitabine  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cystectomyj 
 
 
 
 
 
 
 
 
 
 
X 
 
 
a: Subjects must be screened within 30 days prior to Cycle 1 Day 1 with the exception of some labs.  
b: For Cis/Gem and Carbo/Gem cohorts there must be at least 7 days between Day 1 and Day 8. 
c: Efforts should be made to conduct study visits on the day scheduled (+2 days). Delays in dosing will shift the following cycle so that there are at least 12 days 
between Day 8 of the previous cycle and Day 1 of the current cycle. 
d: Assessments will include vital signs (resting BP HR, RR, and body temperature) and weight.  Height will be recorded at screening.  
e: PET CT for subjects with impaired renal function is an acceptable alternative.   
f:  within 28 days of Cycle 1 Day 1 
g: ECGs should be obtained after the subject has been in a supine position for 5 minutes and recorded while the subject remains in that position.  In case of 
clinically significant ECG abnormalities, including a QTcF value > 470 ms; 2 additional 12 lead ECGs should be obtained over a brief period (eg, 30 minutes) to 
confirm the finding. 
h: Informed consent may be obtained greater than 30 days prior to first dose of study treatment. 
i: Magnesium is to be performed at baseline on Day 1 and as clinically indicated 
j: Within 6 weeks post completion of 4 cycles  
k: Biomarkers sample to be collected at pre-initiation of neoadjuvant treatment, upon completion of neoadjuvant treatment and prior to surgical cystectomy,  4 
weeks (+/- 2 weeks) post-cystectomy and 12 weeks (+/- 2 weeks) post cystectomy 
L: May be completed within 7 days before the End of Study visit  
m: within 4 weeks ± 2 weeks of completion of neoadjuvant treatment, typically at the subject’s cystectomy pre-operative visit 
 
 
 

Amendment 5  IRB-48062 
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31 JAN 2020 
10. 
MEASUREMENTS 
 
10.1  Primary Outcome measures 
The safety and tolerability of durvalumab in combination with chemotherapy in subjects with variant 
histology bladder cancer who initiate study treatment will be assessed as the number, by treatment 
cohort, of Grade 3, 4, or 5 adverse events, considered probably or definitely related by the 
investigator.  The outcome will be reported as a number.  
Time Frame: 120 days  
• 
Safety Issue:  Is this outcome measure assessing a safety issue?  Yes 
10.2  Secondary Outcome measures 
The number and proportion of subjects who initiate study treatment and achieve tumor stage of 
pT2 N0 M0 or better (eg, pT0, pT1 N0) at cystectomy.  
T0  N0  M0 =  No evidence of primary tumor 
T1  N0  M0 = Tumor staging by pathological assessment detected in lamina propria (T0), with 
no tumor-positive nodes (N0).  
T2 N0 M0 = Tumor staging by pathological assessment detected in muscularis propria (pT2), 
with no tumor-positive nodes (N0) or tumor metastases (M0) observed.   
Time Frame: 20 weeks 
• 
Safety Issue:  Is this outcome measure assessing a safety issue?  No 
See also Appendix 2 National Comprehensive Cancer Network Bladder Cancer Guidelines.  
10.2.1  Secondary Outcome Measurement Definition 
• 
Pathological review 
10.2.2 Secondary Outcome Measurement Methods 
Pathologists standard assessment of cystectomy with pathologic T stage assessment 
10.2.3 Secondary Outcome Measurement Time Points:   
Post-combination treatment of durvalumab and neoadjuvant chemotherapy for a maximum of four 
cycles followed by cystectomy 
11. 
REGULATORY CONSIDERATIONS 
11.1 Institutional Review of Protocol 
The protocol and the proposed informed consent will be reviewed and approved by the Stanford 
IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB prior to implementation.  
11.2 Data and Safety Monitoring Plan  
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring 
entity for this study.  The DSMC will audit study-related activities to determine whether the study 
has been conducted in accordance with the protocol, local standard operating procedures, FDA 

Amendment 5  IRB-48062 
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31 JAN 2020 
regulations, and Good Clinical Practice (GCP).  This may include review of the following types of 
documents participating in the study: regulatory binders, case report forms, eligibility checklists, and 
source documents.  In addition, the DSMC will regularly review serious adverse events and protocol 
deviations associated with the research to ensure the protection of human subjects.  Results of the 
DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time 
of continuing review, or in an expedited fashion, as needed.  
11.3 Data Management Plan 
Case Report Forms (CRFs) are printed or electronic documents designed to record all 
protocol-related information on each trial participant.  CRFs should summarize the clinical findings 
and observations necessary to ensure safety of participants on the study, and to document the 
study outcomes.  CRFs are required by the SRC for all Interventional studies.  CRF design and 
creation must be completed prior to enrollment of the first participant.  OnCore will be used for 
CRF’s.  
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document treatment outcomes for data analysis.  Case report forms will 
be developed using the Online Collaborative Research Environment (OnCore) database system 
and will be maintained by study team.  CRFs will be kept in a locked office, only accessible to the 
research team.  
12. 
STATISTICAL CONSIDERATIONS 
12.1 No interim analysis is planned 
12.2.1 
Analysis Population 
Primary 
All subjects who initiate study treatment will be included in the safety analysis (primary objective 
and outcome).   
We set the null hypothesis of 1% for the proportion of patients experiencing a grade 3 or greater 
adverse event. Our sample size has 71% power at the alternative of 10%. Calculation based on 
binomial probabilities using a one-sided significance level of 5%. The trial will be deemed a success 
if no more than 2 patients experience a grade 3 or greater immune-related adverse event out of 24.  
Precision: A sample of 24 patients will allow proportions to be estimated with a margin of error no 
larger than plus or minus 21 percentage points.  The margin is expected to be smaller.  For 
example if none of the 24 patients experience grade 3 or greater toxicity, we will be able to 
conclude with 95% confidence that the true rate is not larger than 17%. 
Secondary 
All subjects undergoing cystectomy will be included for analysis.  Subjects who complete treatment 
but fail to under cystectomy will be considered inevaluable for endpoint analysis for that reason.  
12.2.2  Analysis Plan 
Primary 
Safety data will be collected and assesses by CTCAE v5.   

Amendment 5  IRB-48062 
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31 JAN 2020 
Secondary 
Achievement of tumor staging will be determined by pathologist at cystectomy, and reported by 
treatment cohort.  See also Appendix 2 National Comprehensive Cancer Network Bladder Cancer 
Guidelines.  
In addition, molecular characterization of tissue pre- and post-cystectomy will be analyzed.  
Circulating ctDNA will be collected at baseline and at set time points.  
12.3  Sample Size  
12.3.1 Accrual estimates  
We expect to enroll 12 subjects/year, for a 2 year enrollment of 24 subjects.  
12.3.2 Sample size justification 
This study will include 24 subjects.  
12.3.3 Effect size justification 
Variant histology bladder cancer subjects are not a well-studied population and are usually 
excluded from phase 3 studies.  In traditional urothelial cancer, the percent of subjects achieving 
pT0 is 30%.  We hope to improve this level of subjects achieving pT0 with the additional use of 
immunotherapy.  
12.4 Criteria for future studies 
If pT0 exceeds 50% we will then pursue a fully-powered study.  

Amendment 5  IRB-48062 
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Amendment 5  IRB-48062 
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31 JAN 2020 
14.1. APPENDIX 1.  Dosing Modification and Toxicity Management Guidelines  
Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions 
(Durvalumab Monotherapy) 1 November 2017 Version.  
General Considerations 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study 
drug/study regimen will be made to manage 
potential immune-related AEs based on severity of 
treatment-emergent toxicities graded per 
NCI CTCAE v5. 
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. 
Subjects 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 subject is clinically stable as 
per Investigator or treating 
physician’s clinical judgement. 
3. Doses of prednisone are at 
≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, 
study drug/study regimen may be 
permanently discontinued.  Please 
refer to guidelines below. 
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, subjects should be 
thoroughly evaluated to rule out any alternative 
etiology (eg, 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, eg, myocarditis, or other similar 
events even if they are not currently noted in the 
guidelines – should progress rapidly to high dose 
IV corticosteroids (methylprednisolone at 
2 to 4 mg/kg/day) even if the event is Grade 2, 
and if clinical suspicion is high and/or there has 
been clinical confirmation.  Consider, as 
necessary, discussing with the study physician, 
and promptly pursue specialist consultation. 
• 
If symptoms recur or worsen during corticosteroid 
tapering (28 days of taper), increase the 
corticosteroid dose (prednisone dose [eg, up to 
2 to 4 mg/kg/day PO or IV equivalent]) until 
stabilization or improvement of symptoms, then 
resume corticosteroid tapering at a slower rate 
(> 28 days of taper). 
• 
More potent immunosuppressives such as TNF 
inhibitors (eg, infliximab) (also refer to the 
individual sections of the imAEs for specific type of 

Amendment 5  IRB-48062 
Page 65 of 66 
31 JAN 2020 
Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions 
(Durvalumab Monotherapy) 1 November 2017 Version.  
General Considerations 
Dose Modifications 
Toxicity Management 
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, 
eg, 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, eg, 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 
(ie, hyperthyroidism, hypothyroidism, Type 1 
diabetes mellitus).  
immunosuppressive) should be considered for 
events not responding to systemic steroids.  
Progression to use of more potent 
immunosuppressives should proceed more rapidly 
in events with high likelihood for morbidity and/or 
mortality, eg, 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 
(eg, inflammatory reaction at sites of metastatic 
disease and lymph nodes).  Continuation of study 
drug/study regimen in this situation should be 
based upon a benefit-risk analysis for that subject. 
 

Amendment 5  IRB-48062 
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31 JAN 2020 
14.2. APPENDIX 2.  National Comprehensive Cancer Network Bladder Cancer Guidelines