Clinical trial NCT02844816
Conditions: Recurrent Bladder Urothelial Carcinoma Stage 0a Bladder Urothelial Carcinoma AJCC v6 and v7 Stage 0is Bladder Urothelial Carcinoma AJCC v6 and v7 Stage I Bladder Urothelial Carcinoma AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)
Start date: 2017-03-13; Completion date: 2024-06-26
Enrollment: 172 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well atezolizumab works in treating patients with non-muscle invasive bladder cancer that has come back (recurrent) and has not responded to treatment (refractory) with Bacillus Calmette-Guerin (BCG). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed description:
PRIMARY OBJECTIVE:

I. To estimate complete response at 25 weeks after registration for those with a carcinoma in situ (CIS) component and to evaluate event-free survival at 18 months in patients with BCG-unresponsive high-risk non-muscle invasive bladder cancer (Ta/T1/CIS) treated with atezolizumab.

SECONDARY OBJECTIVES:

I. To estimate event-free survival at 18 months for the subset of patients with papillary cancer (Ta/T1).

II. To estimate progression-free survival, cystectomy-free survival, bladder cancer-specific survival, overall survival in all patients.

ADDITIONAL OBJECTIVES:

I. To estimate the level of agreement between local and central pathology review in terms of recurrence (for all patients) and complete response (for the CIS subset).

II. To identify markers that predict response to atezolizumab in the CIS population and that are associated with event-free survival (EFS) in patients with Ta/T1/CIS BCG-unresponsive non-muscle invasive bladder cancer. The following markers will be tested:

IIIa. Expression of PD-L1 and CD8 by immunohistochemistry (IHC). IIIb. Expression of immune signatures by ribonucleic acid (RNA)-sequencing (RNA-seq).

IIIc. Peripheral immune response by mass cytometry (CyTOF) and TruCulture.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 21 days for up to 17 cycles (51 weeks) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years and then every 24 weeks for 3 years.

Arms: arm 1: Patients receive atezolizumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 17 cycles (51 weeks) in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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PRIVILEGED COMMUNICATION 
Activation Date February 7, 2017 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
TITLE 
 
PHASE II TRIAL OF ATEZOLIZUMAB IN BCG-UNRESPONSIVE 
NON-MUSCLE INVASIVE BLADDER CANCER 
 
This is an FDA Registration Trial. Additional site requirements include maintenance of a Trial Master File 
(https://www.swog.org/sites/default/files/docs/2017-10/Guidance on FDA Inspection.pdf) and additional 
monitoring (see Appendix 18.2). 
 
 
NCT #02844816 
 
STUDY CHAIRS: 
AGENTS: 
 
Principal Investigator: 
NCI Supplied Investigational Agents 
Peter C.V. Black, M.D. (Urology) 
     (CTEP-IND #131515): 
BC Cancer Agency - Vancouver Centre 
Atezolizumab (NSC # 783608) 
600 West 10th Avenue 
 
Vancouver, BC V5Z 4E6 
 
Phone:  605/875-4301 
 
Fax:  604/875-5677 
 
E-mail: pblack@mail.ubc.ca  
 
 
 
Parminder Singh, M.D. (Medical Oncology) 
 
Mayo Clinic Arizona 
 
5881 E. Mayo Boulevard 
 
Phoenix, AZ 85054 
 
Phone: 480/342-4800 
 
Fax: 480/301-4675 
 
Email: Singh.Parminder@mayo.edu   
 
 
 
Seth P. Lerner, M.D. (Urology) 
PATIENT ADVOCATE: 
Scott Department of Urology  
 
Baylor College of Medicine  
Rick Bangs 
7200 Cambridge  
Phone:  248/377-4290 
Houston, TX 77030  
E-mail: chezrick@comcast.net  
Phone: 713/798-6841  
 
Fax: 713/798-5553  
 
E-mail: slerner@bcm.edu  
 
 
BIOSTATISTICIANS: 
TRANSLATIONAL STUDY CHAIR: 
Cathy M. Tangen, Dr.P.H. (Biostatistics) 
 
Michael C. Wu, Ph.D. (Translational Studies) 
David J. McConkey, Ph.D. 
Melissa Plets, M.S. 
Johns Hopkins Greenberg Bladder Cancer Institute 
SWOG Statistics and Data Management Center 
Brady Urological Institute at Johns Hopkins 
Fred Hutchinson Cancer Research Center 
600 North Wolfe Street,  
1100 Fairview Avenue North, M3-C102 
Marburg Building / Suite 149 
P.O. Box 19024 
Baltimore, MD 21287-2101 
Seattle, WA 98109-1024 
Phone: 410/502-4149 
Phone:  206/667-4623 
Fax: 410/614-7526 
Fax:  206/667-4408 
Email: djmcconkey@jhmi.edu   
E-mail: ctangen@fredhutch.org  
 
E-mail: mcwu@fredhutch.org  
 
E-mail: mplets@fredhutch.org  


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PATHOLOGY STUDY CHAIR: 
CCTG CHAMPION: 
 
 
M. Scott Lucia, M.D. 
Wassim Kassouf, M.D. 
University of Colorado HSC 
McGill University Health Center 
Department of Pathology, Mail Stop 8104 
1001 Decarie Blvd, D02.7210 
12801 East 17th Avenue, Rm L18-5103 
Montreal QC H4A 3J1 
P.O. Box 6511 
Phone: 514/934-8246 
 
Aurora, CO 80045 
Fax: 514/934-8297 
Phone: 303/724-3470 
Email: Wassim.kassouf@mcgill.ca   
Fax: 303/724-1427 
 
E-mail: scott.lucia@ucdenver.edu  
 
ALLIANCE CHAMPION: 
 
Sima Porten, M.D. 
University of California San Francisco 
Department of Urology 
550 16th Street, 6th Floor 
San Francisco, CA  94143 
Phone: 415/272-6949 
Fax: 415/476-5366 
Email: sima.porten@ucsf.edu   
 
ECOG-ACRIN CHAMPION: 
 
Trinity Bivilacqua, M.D., Ph.D. 
Johns Hopkins University  
600 N. Wolfe Street, Marburg 409  
Baltimore, MD 21287   
Phone: 443/287-0385  
Fax: 410/614-3695 
Email: tbivala1@jhmi.edu    
 
 
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
CCTG/Canadian Cancer Trials Group  
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
CCTG/Canadian Cancer Trials Group 
 
 
 


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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective(s) ......................................................................................................................... 7 
1.2 
Secondary Objective(s) .................................................................................................................... 7 
1.3 
Additional Objective(s) ..................................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................................... 7 
3.0 
DRUG INFORMATION .................................................................................................................. 10 
3.1 
Atezolizumab (NSC # 783608) (IND #TBD)................................................................................... 11 
4.0 
STAGING CRITERIA ..................................................................................................................... 19 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 19 
5.1 
Study Chair Approval Requirement ............................................................................................... 20 
5.2 
Disease Related Criteria ................................................................................................................ 20 
5.3 
Prior/Concurrent Therapy Criteria .................................................................................................. 21 
5.4 
Clinical/Laboratory Criteria ............................................................................................................. 22 
5.5 
Specimen Submission Criteria ....................................................................................................... 24 
5.6 
Regulatory Criteria ......................................................................................................................... 24 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 24 
7.0 
TREATMENT PLAN ...................................................................................................................... 24 
7.1 
Pre-Medication ............................................................................................................................... 24 
7.2 
Treatment ....................................................................................................................................... 24 
7.3 
Disease Assessment ...................................................................................................................... 26 
7.4 
Prohibited and Cautionary Medications .......................................................................................... 27 
7.5 
Criteria for Removal from Protocol Treatment ............................................................................... 27 
7.6 
Discontinuation of Treatment ......................................................................................................... 28 
7.7 
Follow-Up Period ............................................................................................................................ 28 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 28 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 28 
8.2 
General Adverse Event Management and Dose Modification Guidelines ..................................... 28 
8.3 
Management of Specific AEs ......................................................................................................... 30 
8.4 
Dose Modification Contacts ........................................................................................................... 40 
8.5 
Adverse Event Reporting ............................................................................................................... 40 
9.0 
STUDY CALENDAR ...................................................................................................................... 41 
9.1 
TREATMENT AND SPECIMEN SUBMISSION ............................................................................. 41 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 44 
10.1 
Complete Response ....................................................................................................................... 44 
10.2 
Complete Response duration ........................................................................................................ 44 
10.3 
Progression .................................................................................................................................... 44 
10.4 
Event .............................................................................................................................................. 44 
10.5 
Recurrence ..................................................................................................................................... 44 
10.6 
Progression-Free Survival ............................................................................................................. 44 
10.7 
Event-Free Survival ........................................................................................................................ 44 
10.8 
Recurrence-Free Survival .............................................................................................................. 44 
10.9 
Cancer-Specific Survival ................................................................................................................ 45 
10.10 
Overall Survival .............................................................................................................................. 45 
10.11 
Performance Status ....................................................................................................................... 45 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 45 
11.1 
Patient Populations ........................................................................................................................ 45 
11.2 
Estimate of Sample Size: ............................................................................................................... 46 
11.3 
Analysis: ......................................................................................................................................... 46 
11.4 
Estimate of Accrual Rate................................................................................................................ 47 
11.5 
Statistical Plan for Translational Aims ............................................................................................ 47 
11.6 
Data and Safety Monitoring Committee ......................................................................................... 48 


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12.0 
DISCIPLINE REVIEW .................................................................................................................... 49 
12.1 
Central Pathology Review .............................................................................................................. 49 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 50 
13.1 
Registration Timing ........................................................................................................................ 50 
13.2 
Investigator/Site Registration ......................................................................................................... 50 
13.3 
OPEN Registration Requirements ................................................................................................. 53 
13.4 
Registration Procedures................................................................................................................. 55 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 55 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 55 
14.1 
Data Submission Requirement ...................................................................................................... 55 
14.2 
Master Forms ................................................................................................................................. 55 
14.3 
Data Submission Procedures ........................................................................................................ 56 
14.4 
Data Submission Overview and Timepoints .................................................................................. 57 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 61 
15.1 
Translational Medicine and Banking .............................................................................................. 61 
15.2 
Submission of Images for Banking (Required) .............................................................................. 64 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 67 
16.1 
Adverse Event Reporting Requirements ........................................................................................ 69 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 75 
18.0 
APPENDIX ..................................................................................................................................... 78 
18.1 
Translational Medicine Studies ...................................................................................................... 79 
18.2 
Specimen Banking and Translational Medicine Material Instructions for SWOG Biospecimen 
Bank (BB) ....................................................................................................................................... 88 
18.3 
Quality Assurance Auditing and Monitoring ................................................................................... 89 
18.4 
S1605 Pre-Registration Study Chair Approval Form ..................................................................... 96 
18.5 
Investigator Electronic Signature ................................................................................................... 98 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal: 
 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
at 866-651-2878 to receive 
further information and support.   
 
Contact the CTSU Regulatory 
Help Desk at 866-651-2878 for 
regulatory assistance. 
 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org.  
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com.  
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench. Access this by 
using your active CTEP-IAM 
userid and password at the 
following url: 
 
https://crawb.crab.org/TXWB/cts
ulogon.aspx  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
 
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center by phone or email: 
206/652-2267 
guquestion@crab.org  
For treatment or toxicity related questions contact the Study Chair by phone or email: (Dr. Peter C.V. 
Black at 605/875-4301) 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org.  
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Cystoscopy and cytology performed as specified in the study calendar (see Section 9.0).  Mandatory 
biopsy at Week 25 for patients with any CIS component. 
BCG unresponsive high-risk non-
muscle invasive (Ta/T1/CIS) 
bladder cancer (TURBT) 
Registration 
Stratify by CIS disease component 
at registration: 
Present vs. Absent 
Follow-up 
Maximum 5 years 
from registration 
Atezolizumab for 
17 cycles (51 weeks)* 
Obtain signed S1605 Pre-Registration 
Study Chair Approval form from Drs. 
Black or Singh prior to registration 


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1.0 
OBJECTIVES 
 
1.1 
Primary Objective(s) 
 
a. 
To estimate complete response at 25 weeks after registration for those with a CIS 
component and to evaluate event-free survival at 18 months in patients with BCG-
unresponsive high-risk non-muscle invasive bladder cancer (Ta/T1/CIS) treated 
with atezolizumab. 
 
1.2 
Secondary Objective(s) 
 
a. 
To estimate event-free survival at 18 months for the subset of patients with 
papillary cancer (Ta/T1). 
 
b. 
To estimate progression-free survival, cystectomy-free survival, bladder cancer-
specific survival, overall survival in all patients. 
 
1.3 
Additional Objective(s) 
 
a. 
To estimate the level of agreement between local and central pathology review in 
terms of recurrence (for all patients) and complete response (for the CIS subset). 
 
b. 
To identify markers that predict response to atezolizumab in the CIS population 
and that are associated with EFS in patients with Ta/T1/CIS BCG-unresponsive 
non-muscle invasive bladder cancer.  The following markers will be tested: 
 
• 
Expression of PD-L1 and CD8 by immunohistochemistry (IHC) 
• 
Expression of immune signatures by RNA-sequencing (RNA-seq) 
• 
Peripheral immune response by mass cytometry (CyTOF) and TruCulture 
 
 
2.0 
BACKGROUND 
 
Defining the Clinical Unmet Need 
 
Bladder cancer is a common malignancy with over 75,000 new cases diagnosed every year in the 
United States.  (1)  Seventy percent or more of these patients are diagnosed at an early stage with 
non-muscle invasive bladder cancer (NMIBC).  Around 15-20% of these patients are at high risk 
(30-40%) of progression to muscle invasive bladder cancer (MIBC), which has a significant 
negative impact on survival. (2) Patients with high-grade Ta or T1 papillary disease or carcinoma 
in situ (CIS) constitute the majority of these high-risk patients.  (3) 
 
For the past 35 years the standard of care for patients with high-risk NMIBC has been complete 
transurethral resection (biopsy only for CIS) followed by intravesical immunotherapy with Bacillus 
Calmette-Guerin (BCG).  (4)  Although 75-80% patients will have an initial complete response in 
the case of CIS with or without papillary disease, or be free of recurrence six months from initiating 
treatment, at least one third of these patients will recur.  (5)  Some patients may be treated 
effectively with additional BCG with or without interferon, but a third course of BCG is regarded as 
ineffective.  (6)  Cookson and colleagues reported that 53% of high-risk patients ultimately 
progressed to cystectomy or died from their disease with 15-year median follow-up.  (7) 
 
In a randomized Phase II trial of BCG unresponsive patients, 80 subjects were randomized to 
gemcitabine versus repeat BCG. (8) At two years, recurrence free survival was 19% in the 
gemcitabine arm and 3% in the BCG arm (p < 0.008).  Thirty-three percent in the gemcitabine arm 
and 37.5% in the BCG arm had progression of disease and underwent radical cystectomy.  This 
study validates the expert consensus that trials in BCG-unresponsive patients should not include a 
control arm consisting of BCG alone.  (9,10,11) 
 


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Valrubicin is the only FDA approved treatment for BCG unresponsive CIS.  (12)  A single arm 
Phase II study evaluated the activity of intravesical valrubicin in 90 patients with carcinoma in situ 
who had failed prior BCG with or without other subsequent intravesical therapies.  The trial 
demonstrated a 21% complete response rate at six months and only 8% disease-free rate at 30 
months.  Life table analysis on the data from this trial demonstrated that the likelihood of being 
disease free at 12 months was only 17%.  (13)  This trial led to the approval of valrubicin by the 
FDA for this indication.  This trial exemplifies the precedence of drug approval in this setting based 
on Phase II data. 
 
In a SWOG-led single arm Phase II clinical trial, S0353, 58 patients were enrolled to test the activity 
of intravesical gemcitabine induction followed by maintenance in patients with BCG unresponsive 
NMIBC.  Eligible patients had recurrent NMIBC following two induction courses of BCG (6+6) or 
induction plus at least one maintenance cycle (6+3).  Forty-seven patients were evaluable for 
response.  At three months and two years, 47% and 21%, respectively, were free of recurrence.  
The trial demonstrated the activity of intravesical gemcitabine; however, the poor durability of 
response with maintenance therapy emphasizes the need for newer treatment options.  (14) 
 
Intravesical chemotherapy with other agents, including mitomycin, docetaxel, or doxorubicin is 
considered inferior to BCG therapy in high-risk disease, and its efficacy in the second line setting 
is uniformly poor with two-year recurrence- free survival rates typically below 20%.  (15)  Radiation 
is only rarely administered for high-grade T1 disease, although there is an ongoing clinical trial 
evaluating the efficacy of this approach (RTOG 0926). 
 
In patients who progress to muscle invasive disease, the bladder cancer specific death rate at 10 
years has been reported to be approximately 50%.  (16)  Radical cystectomy is therefore 
considered the standard of care for any patient with BCG-unresponsive high-grade NMIBC.  (17)  
Even in the best surgical hands this procedure entails high morbidity (up to 60%) and risk of 
mortality (2.7 to 9%).  (18,19)  Many patients are medically unfit for cystectomy and others refuse 
the surgery.  In all cases cystectomy has a significant impact on quality of life.  There is thus an 
urgent need for new treatments that offer these patients the opportunity to preserve their bladders 
with an acceptably low risk of progression. 
 
Rationale for Checkpoint Inhibition in High-Risk Non-Muscle Invasive Bladder Cancer 
 
Intravesical BCG has demonstrated modest efficacy in preventing recurrence and progression to 
muscle invasive bladder cancer (MIBC).  While the mechanism of action of BCG has not been fully 
elucidated, the need for an intact immune system is well recognized.  When NMIBC becomes 
refractory to BCG, the implication is that the disease is able to evade the BCG-induced immune 
response.  Recent evidence in tumor-mediated immune evasion has highlighted the negative 
immune checkpoint termed programmed death (PD)-1.  Blockade of the PD-1 axis mediates anti-
neoplastic activity by promoting effector function of tumor infiltrating immune cells, which recognize 
cancer neoantigens as foreign but are maintained in an anergic state via negative co-signaling from 
the immune checkpoint expressed in the malignant milieu, expressed on both immune cells and 
tumor cells themselves (the cancer-immunity cycle).  (20.21) 
 
Strong clinical evidence is mounting for efficacy of monoclonal antibody blockade of either PD-1 or 
its ligands (PD-L1 and PD-L2) in patients with advanced urothelial carcinoma of the bladder and 
upper urinary tract.  In particular, the anti-PD-L1 antibody atezolizumab (Genentech) was recently 
approved by the FDA for second-line therapy after prior cisplatin-based chemotherapy in patients 
with advanced urothelial carcinoma. 
 
Breakthrough status for atezolizumab was initially granted by the FDA based on results from a 
large Phase I trial with an adaptive design that included an expansion arm of 68 patients with pre-
treated metastatic urothelial carcinoma. (22) These results were subsequently updated at ASCO 
2015. (23) An objective response was observed in 43% (46% in update) of patients with high 
expression of PD-L1 in their tumor infiltrating immune cells, compared to 11% (16% in update) in 
patients with low expression. Complete response was observed in 7% of patients, all of whom had 
high PD-L1 expression. The drug was well tolerated with only 3% of patients experiencing Grade 


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3-4 toxicities (8% in update), which were predominantly asthenia, thrombocytopenia, and 
electrolyte abnormality. (24)  
 
Results from a Phase II clinical trial of atezolizumab in patients with metastatic urothelial carcinoma 
progressing on cisplatin-based chemotherapy were published more recently. (25) Of 311 patients 
included on the trial, 100 were considered positive (2-3+) for PD-L1. The overall response rate 
(ORR) was 15% for the entire cohort and 26% for the positive patients. Thirty-eight of 45 (84%) 
responding patients were still responding to therapy at the time of data cut-off. Grade 3-4 adverse 
events were observed in 16% of patients. A large (767 patient) multicenter Phase III trial with the 
same agent has completed accrual in the metastatic setting after prior failure of cisplatin-based 
chemotherapy, but has not yet been reported. 
 
A third trial tested the PD-1 inhibitor pembrolizumab in the same setting with similar results.  (26)  
Only patients with PD-L1 expression were included, and the ORR was 25% in 28 evaluable 
patients.  Avelumab, another PD-L1 inhibitor, was tested in a Phase 1b trial in 129 unselected 
patients with metastatic or locally advanced urothelial carcinoma; the ORR was 16.5%. (27,28) PD-
L1 expression in tumor-infiltrating immune cells in bladder tumors has been predictive of ORR in 
these trials.  Nivolumab, another PD-1 inhibitor, showed comparable results in an early report in 
the metastatic setting.  (29) 
 
The first Phase III data for checkpoint blockade in urothelial carcinoma has not yet been reported, 
but October 21, 2016 Merck announced that their randomized Phase III trial comparing 
pembrolizumab to investigator’s choice chemotherapy (Keynote 045 Trial) in the second line for 
patients with metastatic urothelial carcinoma was halted early due to superiority of the 
pembrolizumab arm.  (30) 
 
Two studies have demonstrated that PD-L1 is also expressed in NMIBC.  An analysis by Inman et 
al. included 44 BCG-treated patients with NMIBC, of whom 16 developed recurrent disease.  The 
initial TNM stages of these 16 patients were pTa in 10 cases, pT1 in 3 cases, and CIS in 3 cases.  
Only three of these patients were PD-L1-positive in the original tumor specimen, but 12 of the 16 
recurrences had BCG granulomata, and 11 of these granulomata showed a pattern of diffuse and 
intense (> 90% of cells) PD-L1 staining.  Hurwitz et al. measured PD-L1 expression in a cohort of 
39 patients who underwent at least two transurethral resections of bladder tumor (TURBT) for first 
and recurrent NMIBC, of whom 23 received intravesical BCG between the first and second TURBT.  
PD-L1 was detected in seven of 39 patients with first TURBT, 12 of 39 with second TURBT, and 
seven of 13 with third TURBT.  The authors concluded that PD-L1 expression was associated with 
the number of recurrences, but not with BCG therapy. (31,32,33) 
 
Checkpoint inhibitors have been studied in pre-clinical models of NMIBC.  Mangsbo et al. have 
tested combined inhibition of anti-CTLA4 with either anti-PD-L1 or anti-PD-1 in a syngeneic model 
of NMIBC.  (34)  These agents caused an increase in tumor-reactive T-cells in circulation and a 
decrease in regulatory T-cells in tumor tissue, which was reflected in clear inhibition of tumor growth 
and improved mouse survival.  Avelumab (anti-PD-L1) similarly inhibited tumor growth and 
improved mouse survival in a recent presentation by Vandeveer et al.  (35)  Finally, de Boisferon 
et al. observed better efficacy of systemic PD-1 inhibition compared to intravesical BCG in a 
syngeneic mouse model.  (36) 
 
Blockade of the PD-1 axis in high-grade NMIBC (Ta, T1, and CIS) has not been investigated to 
date.  The best clinical data on the use of checkpoint inhibitors in NMIBC is derived from a small 
trial that tested ipilumimab (CTLA4 inhibitor) in 12 patients with T1 and T2 bladder cancer prior to 
radical cystectomy.  (37)  The primary endpoints of this trial were safety and immune monitoring.  
The expression of ICOS (“inducible costimulator”) in CD4+ T-cells is considered a 
pharmacodynamic marker of ipilumimab effect.  All patients had an increased frequency of 
CD4+/ICOShi T-cells in both tumor tissues and in the peripheral blood.  These CD4+/ICOShi T cells 
produced IFN-gamma and were shown to recognize tumor antigen (NY-ESO-1).  There was an 
increase in the ratio of effector to regulatory T-cells. 
 
Correlative Markers 
 


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The translational component of this proposal focuses on identification of predictive markers of 
response to anti-PD-L1 therapy. 
 
Virtually every early trial testing a checkpoint inhibitor in metastatic bladder cancer has found that 
response rates are highest in patients with high expression levels of PD-L1 by 
immunohistochemistry (IHC). This holds true also in the Phase I and II trials of atezolizumab after 
prior cisplatin-based chemotherapy.  (38,39) Furthermore, CD8 expression measured by IHC, 
which is a marker of cytotoxic T-cell infiltration, also correlates to response. We will test both IHC 
markers in our patient cohort at baseline and with every subsequent mandatory or for-cause biopsy.   
 
Early phase trials show also that gene expression signatures can predict response to atezolizumab. 
These signatures include proprietary immune signatures developed by Genentech, but also the 
molecular subtypes described by The Cancer Genome Atlas (TCGA).  (40) The TCGA describes 
four clusters that are being referred to increasingly as luminal 1 and 2, and basal 1 and 2. The 
phase II trial of atezolizumab in second-line metastatic urothelial carcinoma revealed that patients 
with luminal 2 (also known as “immune infiltrated luminal”) subtype have the highest rate of 
response. Basal 2 tumors (with even higher immune infiltration) have intermediate response, and 
luminal 1 and basal 1 tumors demonstrate a low response rate. A recent paper confirmed that the 
same molecular subtypes can be found also in NMIBC. We will test the immune signatures and 
subtypes in our cohort of BCG unresponsive high risk NMIBC patients and correlate these to 
response to therapy. For further details see Section 18.1. 
 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below. 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
3 
9 
0 
0 
12 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
11 
16 
0 
0 
27 
White 
42 
92 
4 
3 
141 
More Than One Race 
0 
3 
0 
0 
3 
Total 
56 
120 
4 
3 
183 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
1 
0 
0 
1 
White 
6 
11 
0 
0 
17 
More Than One Race 
0 
0 
0 
0 
0 
Total 
6 
13 
0 
0 
19 
 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures 


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For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, atezolizumab is investigational and is being provided under an IND held by the 
National Cancer Institute.  The Investigator Brochure may be obtained by contacting the NCI’s 
Pharmaceutical Management Branch (PMB) at 240/276-6575. 
 
3.1 
Atezolizumab (NSC # 783608) (IND #TBD) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action:  Atezolizumab is a humanized immunoglobulin (IgG1) 
monoclonal antibody that is produced in Chinese hamster ovary (CHO) cells.  
Atezolizumab targets programmed death-ligand 1 (PD-L1) on immune cells or 
tumor cells and prevents interaction with either programmed death-1 (PD-1) 
receptor or B7.1 (CD80), both of which function as inhibitory receptors expressed 
on T cells.  Interference of the PD-L1:PD-1 and PD-L1:B7.1 interactions may 
enhance the magnitude and quality of the tumor-specific T-cell response through 
increased T-cell priming, expansion, and/or effector function.  Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid substitution at 
position 298 on the heavy chain, which results in a non-glycosylated antibody that 
has minimal binding to Fc receptors and, consequently, eliminates detectable Fc‑
effector function.  By eliminating Fc-effector function and antibody dependent cell-
mediated cytotoxicity (ADCC), antibody-mediated clearance of activated effector 
T cells is also eliminated.  Atezolizumab shows anti-tumor activity in both 
nonclinical models and cancer patients, and is being investigated as a potential 
therapy in a wide variety of malignancies. 
 
b. 
PHARMACOKINETICS 
 
On the basis of available preliminary PK data (0.03-20 mg/kg), atezolizumab 
appeared to show linear pharmacokinetics at doses ≥ 1 mg/kg.  For the 1 mg/kg 
and 20 mg/kg dose groups, the mean apparent CL and the mean Vss had a range 
of 3.20 to 4.44 mL/day/kg and 48.1 to 65.7 mL/kg, respectively, which is consistent 
with the expected profile of an IgG1 antibody in humans. 
 
Serum atezolizumab concentrations exhibited a biphasic disposition with an initial 
rapid distribution phase followed by a slow elimination phase.  Atezolizumab 
exhibited nonlinear pharmacokinetics at doses <1 mg/kg (i.e., 0.03-0.3 mg/kg), 
likely due to target-mediated CL at lower concentrations.  Atezolizumab exhibited 
linear pharmacokinetics at doses ≥ 1 mg/kg.  At doses ≥ 1 mg/kg, the mean Cmax 
increased in a dose-proportional manner and was 26.0 mcg/mL for the 1-mg/kg 
dose group and 472 mcg/mL for the 20 mg/kg dose group.  Similarly, at doses ≥ 1 
mg/kg, the group mean AUC0-∞ had a range of 340-6050 Day x mcg/mL for 1 
mg/kg and 20 mg/kg dose group and was approximately dose proportional, by 
similar CL across the dose range.  The observed CL and Vss for atezolizumab at 
doses ≥ 1 mg/kg are consistent with these of a typical IgG1 antibody in humans. 
 
Currently available PK and ATA data from Study PCD4989g suggest that the 
15-mg/kg atezolizumab q3w regimen (or fixed-dose equivalent) for Phase II and 
Phase III studies would be sufficient to both maintain trough concentration 
(Ctrough) ³ 6 mg/mL and further safeguard against both interpatient variability and 
the potential effect of ATAs that could lead to subtherapeutic levels of 
atezolizumab relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose 
equivalent).  From inspection of available observed Ctrough data, moving further 
to the 20-mg/kg atezolizumab q3w regimen does not appear to be warranted to 
maintain targeted Ctrough levels relative to the proposed 15-mg/kg atezolizumab 
q3w level.  


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Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences 
in exposure following a fixed dose or a dose adjusted for weight.  On the basis of 
this analysis, a fixed dose of 1200 mg has been selected when atezolizumab is 
administered q3w (equivalent to an average body weight-based dose of 
15 mg/kg).  For the every-2-weeks (q2w) dosing interval used in this study, the 
corresponding fixed dose is 800 mg. 
 
Refer to the atezolizumab Investigator’s Brochure for details regarding nonclinical 
and clinical pharmacology of atezolizumab. 
 
c. 
ADVERSE EFFECTS  
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Atezolizumab (MPDL3280A, NSC 783608) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 3,097 patients. 
Below is the CAEPR for Atezolizumab (MPDL3280A). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
Version 2.2, July 23, 20181  
 
 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
CARDIAC DISORDERS 
 
 
 
Heart failure2 
 
 
 
Myocarditis2 
 
 
 
Pericardial 
effusion2 
 
 
 
Pericardial 
tamponade2 
 
 
 
Pericarditis2 
 
ENDOCRINE DISORDERS 
 
 
 
Adrenal 
insufficiency2 
 


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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
 
Endocrine 
disorders - 
Other 
(diabetes)2 
 
 
Hyperthyroidism
2 
 
 
 
 
Hypophysitis2  
 
Hypothyroidism2  
 
EYE DISORDERS 
 
 
 
Eye disorders - 
Other (ocular 
inflammatory 
toxicity)2 
 
 
 
Uveitis2 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain  
Abdominal pain (Gr 2) 
 
 
Colitis2 
 
 
Diarrhea 
 
Diarrhea (Gr 2) 
 
Dysphagia 
 
 
 
Nausea 
 
Nausea (Gr 2) 
 
 
Pancreatitis2 
 
 
Vomiting 
 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
Fatigue 
 
 
Fatigue (Gr 2) 
 
Fever3 
 
 
 
Flu like 
symptoms3 
 
 
HEPATOBILIARY DISORDERS 
 
 
 
Hepatic failure2  
 
 
Hepatobiliary 
disorders - 
Other 
(hepatitis)2 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction3  
 
 
 
Anaphylaxis3 
 
 
 
Cytokine 
release 
syndrome3 
 
 
 
Immune 
system 
disorders - 
Other 
(systemic 
immune 
activation)2 
 
INFECTIONS AND INFESTATIONS 
 


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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
Infection4 
 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS  
 
Infusion related 
reaction3 
 
 
INVESTIGATIONS 
 
 
Alanine 
aminotransferas
e increased2 
 
 
 
Alkaline 
phosphatase 
increased2 
 
 
 
Aspartate 
aminotransferas
e increased2 
 
 
 
Blood bilirubin 
increased2 
 
 
 
GGT increased2  
 
 
Lipase 
increased* 
 
 
 
 
Platelet count 
decreased 
 
 
Serum amylase 
increased* 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
 
 
Hyperglycemia
2 
 
 
Hypokalemia 
 
 
 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia2 
 
 
 
Back pain 
 
 
 
 
Generalized 
muscle 
weakness 
 
 
Myalgia 
 
 
 
 
Myositis2 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Ataxia2 
 
 
 
Encephalopath
y2 
 
 
 
Nervous 
system 
disorders - 
Other 
(encephalitis 
non-infective)2 
 


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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
 
Guillain-Barre 
syndrome2 
 
 
 
Nervous 
system 
disorders - 
Other 
(meningitis 
non-infective)2 
 
 
 
Myasthenia 
gravis2 
 
 
 
Paresthesia2 
 
 
 
Peripheral 
motor 
neuropathy2 
 
 
 
Peripheral 
sensory 
neuropathy2 
 
RENAL AND URINARY DISORDERS 
 
 
 
Renal and 
urinary 
disorders - 
Other 
(nephritis)2 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS  
 
Cough 
 
Cough (Gr 2) 
 
Dyspnea 
 
 
 
Hypoxia 
 
 
 
Nasal 
congestion 
 
Nasal congestion (Gr 
2) 
 
 
Pleural 
effusion2 
 
 
 
Pneumonitis2 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
 
Bullous 
dermatitis2 
 
 
Pruritus 
 
 
 
Rash acneiform  
 
 
Rash maculo-
papular 
 
 
 
Skin and 
subcutaneous 
tissue disorders 
- Other (lichen 
planus)2 
 
 
*Denotes adverse events that are < 3%. 
 
1 This table will be updated as the toxicity profile of the agent is revised. Updates 
will be distributed to all Principal Investigators at the time of revision. The current 
version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, 


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the name of the investigator, the protocol and the agent should be included in 
the e-mail. 
2 Atezolizumab, being a member of a class of agents involved in the inhibition of 
“immune checkpoints,” may result in severe and possibly fatal immune-mediated 
adverse events probably due to T-cell activation and proliferation. Immune-
mediated adverse reactions have been reported in patients receiving 
atezolizumab. Adverse events potentially related to atezolizumab may be 
manifestations of immune-mediated adverse events. In clinical trials, most 
immune-mediated adverse reactions were reversible and managed with 
interruptions of atezolizumab, administration of corticosteroids and supportive 
care. 
3 Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, 
and cytokine release syndrome, which have been observed following 
administration of atezolizumab, may manifest as fever, chills, shakes, itching, 
rash, hypertension or hypotension, or difficulty breathing during and immediately 
after administration of atezolizumab. 
4 Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
Adverse events reported on atezolizumab (MPDL3280A) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable 
possibility that atezolizumab (MPDL3280A) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Cardiac arrest; Ventricular tachycardia 
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; 
Edema limbs; Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Portal vein thrombosis 
INVESTIGATIONS - Lymphocyte count decreased; Neutrophil count decreased; 
Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis 
syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; 
Muscle cramp: Pain in extremity 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS 
- 
Bronchopulmonary hemorrhage; Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; 
Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
Note: Atezolizumab (MPDL3280A) in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 
 
1. 
Pregnancy and Lactation:  No developmental or reproductive toxicity 
studies have been conducted with atezolizumab as several nonclinical 
studies have already demonstrated that the PD-L1/PD-1 signaling 
pathway is essential in establishing maternal/fetal tolerance, which is 
necessary for embryo-fetal survival during gestation.  Based on the critical 
role that PD-L1/PD1 pathway plays in the maintenance of maternal-fetal 


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tolerance, atezolizumab should not be administered to pregnant women.  
The effects of atezolizumab on human reproduction or on the fetus or the 
developing infant are unknown but expected to have an adverse effect. 
 
It is not known whether atezolizumab is excreted in human milk. However, 
antibodies are known to cross the placenta and are excreted in breast milk 
during lactation.  Atezolizumab should not be administered to nursing 
mothers. 
 
2. 
Drug 
Interactions: 
 
Cytochrome 
P450 
enzymes 
as 
well 
as 
conjugation/glucuronidation reactions are not involved in the metabolism 
of atezolizumab.  No drug interaction studies for atezolizumab have been 
conducted or are planned.  There are no known interactions with other 
medicinal products or other form of interactions. 
 
d. 
DOSING & ADMINISTRATION 
 
1. 
See Section 7.0 Treatment Plan. 
 
e. 
HOW SUPPLIED 
 
1. 
Atezolizumab will be supplied free of charge.  It will be provided by 
Genentech and distributed by CTEP PMB. 
 
2. 
Atezolizumab is supplied in a single-use, 20-mL glass vial as a colorless-
to-slightly-yellow, sterile, preservative-free clear liquid solution intended 
for IV administration. Atezolizumab is formulated as 60 mg/mL 
atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% 
polysorbate 20, at a pH of 5.8.  The vial is designed to deliver 20 mL (1200 
mg) of atezolizumab solution but may contain more than the stated volume 
to enable delivery of the entire 20 mL volume. 
 
Atezolizumab vial size 
Vial volume 
Final concentration 
1200 mg 
20 ml 
60 mg/mL 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Atezolizumab must be refrigerated at 2°C-8°C (36°F- 46°F) upon receipt until use.  
No preservative is used in atezolizumab and therefore, the vial is intended for 
single use only.  Discard any unused portion of drug remaining in a vial.  Vial 
contents should not be frozen or shaken and should be protected from direct 
sunlight. 
 
Atezolizumab (1200 mg per vial) will be administered in 250 mL 0.9% NaCl IV 
infusion bags and infusion lines equipped with 0.2 μm in-line filters. The IV bag 
may be constructed of polyvinyl chloride (PVC) or polyolefin (PO); the IV infusion 
line may be constructed of polyvinyl chloride (PVC) or polyethylene (PE); and the 
0.2 mcm in-line filter may be constructed of polyehersulfone (PES). The use of 
administration supplies composed of materials other than those listed should be 
avoided if possible.  Atezolizumab must be prepared/diluted under appropriate 
aseptic conditions as it does not contain antimicrobial preservatives. The solution 
for infusion should be used immediately to limit microbial growth in case of 
potential accidental contamination. If not used immediately, in-use storage time 
and conditions prior to use are the responsibility of the user. 
 
The dose solution prepared for IV bag delivery may be stored at 2°C to 8°C (36°F 
to 46°F) and/or at room temperature for up to a total in-use storage time of 8 hours. 


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g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug ordering:  Atezolizumab is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis (DCTD), 
NCI.  NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designees) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that the agent 
be shipped directly to the institution where the patient is to be treated.  
PMB does not permit the transfer of agents between institutions (unless 
prior approval from PMB is obtained).  The CTEP assigned protocol 
number must be used for ordering all CTEP supplied investigational 
agents.  The responsible investigator at each participating institution must 
be registered with CTEP, DCTD through an annual submission of FDA 
form 1572 and a CV.  If there are several participating investigators at one 
institution, CTEP supplied investigational agents for the study should be 
ordered under the name of one lead investigator at that institution.  Active 
CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the 
PMB Online Agent Order Processing (OAOP) application https://eapps- 
ctep.nci.nih.gov/OAOP/.  Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account https://eapps-
ctep.nci.nih.gov/iam/ and the maintenance of an “active” account status 
and a “current” password.  For questions about drug orders, transfers 
returns or accountability, call 240/276-6575 Monday through Friday 
between 
8:30 
am 
and 
4:30 
pm 
(ET) 
or 
e-mail 
PMBAfterHours@mail.nih.gov any time. 
 
2. 
Drug Handling and Accountability 
 
Drug Accountability: The investigator, or a responsible party designated 
by the investigator, must maintain a careful record of the receipt, 
disposition, and return of all drugs received from the PMB using the Drug 
Accountability Record Form available on the NCI home page 
(http://ctep.cancer.gov) 
 
a. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
If the trial is a placebo control trial – indicate that separate DARFs 
are needed for each patient to also include the placebo drug 
supply. 
 
 


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b. 
Drug Return and/or Disposition Instruction 
 
i. 
Drug Returns:  All unused drug supplies should be 
recovered to the PMB. When it is necessary to return 
study drug (e.g., sealed vials remaining when expired 
vials are recalled by the PMB), investigators should return 
the study drug to the PMB using the NCI Return Agent 
Form 
available 
on 
the 
NCI 
home 
page 
(http://ctep.cancer.gov). 
ii. 
Drug expiration: (If packaging does not have expiration 
date, check with drug ordering designee and/or PI at site 
to confirm receipt of ongoing stability testing letter from 
NCI. If packaging has expiration date, indicate drug 
expiration date on the DARF under Manufacturer and Lot 
# and use the drug lots with shorter expiration date first) 
 
c. 
Contact Information 
 
Questions about drug orders, transfers, returns or accountability 
should be addressed to the PMB by calling 240/276-6575 Monday 
through Friday between 8:30 am and 4:30 pm Eastern Time. 
 
 
4.0 
STAGING CRITERIA 
 
PRIMARY TUMOR (T) (AJCC Seventh Edition, 2009) 
 
Ta 
Non-invasive papillary carcinoma 
CIS 
Carcinoma in situ:  "flat tumor" 
T1 
Tumor invades subepithelial connective tissue 
 
HISTOLOGIC GRADE (G) 
 
WHO 2004/ISUP 
 
 
 
Low-grade 
 
 
 
 
High-grade 
 
 
 
 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® 
(see Section 14.0).  Any potential eligibility issues should be addressed to the SWOG Statistics and Data 
Management Center in Seattle at 206/652-2267 or guquestion@crab.org prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 3 weeks later would be considered Day 21.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 21 or 42 falls on a weekend 
or holiday, the limit may be extended to the next working day. 
 
 


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5.1 
Study Chair Approval Requirement  
 
Patients’ disease related criteria (Section 5.2) and BCG-unresponsiveness (Section 5.3a) 
must be discussed with at least one of the S1605 Study Chairs prior to registration. The 
S1605 Pre-Registration Study Chair Approval form must be signed by one of the S1605 
Study Chairs to indicate approval within 30 days prior to registration.  
 
The S1605 Pre-Registration Study Chair Approval Form is located in Section 18.4. See 
Section 14.4a for form submission requirements. 
 
5.2 
Disease Related Criteria 
 
a. 
Patients must have histologically proven, recurrent, non-muscle invasive urothelial 
carcinoma of the bladder within 60 days prior to registration. The carcinoma must 
be Stage T1 High-Grade, Stage CIS, or Stage Ta High-Grade (see Section 5.2f for 
high-grade T1). 
 
b. 
Patients with mixed urothelial carcinoma and a glandular and/or squamous 
component will be eligible for the trial, but the presence of other histologic variants, 
pure adenocarcinoma, or pure squamous cell carcinoma, or pure squamous 
carcinoma in situ will make a patient ineligible. 
 
c. 
Patients must have had all visible tumor resected completely within 60 days prior 
to registration. CIS disease is not expected to be completely excised.  All patients 
must have tumor tissue from the histologic diagnosis of recurrence (see Section 
5.2.a) available for central pathology review submission (see Section 12.0). Failure 
to submit these materials will make the patient ineligible for this study. 
 
d. 
Patients must have had cystoscopy confirming no visible papillary tumor within 21 
days prior to registration. (CIS disease is not expected to have been completely 
excised). If the TURBT or bladder biopsy falls within 21 days of registration it will 
fulfill this criterion.  
 
e. 
Patients must have had urine cytology within 21 days prior to registration. Cytology 
for patients with CIS component is not expected to be negative for malignant cells.  
If the cytology for male patients with only Ta/T1 disease in the absence of CIS is 
positive for malignant cells, patient must have had a biopsy of the prostatic urethra 
within the previous six months. 
  
f. 
All patients with T1 urothelial carcinoma at study entry must undergo re-TURBT 
within 60 days prior to registration, and must have evidence of uninvolved 
muscularis propria in the pathologic specimen from either the first or the second 
TURBT. Tissue from the re-resection must be submitted for central review in 
addition to the tissue from the first TURBT (see Section 12.0). The TURBT that 
identified the recurrent T1 disease may have taken place more than 60 days prior 
to registration but not more than 120 days. Patients with high grade Ta or CIS do 
not require a re-TURBT, but if this is performed at the discretion of the treating 
physician, the second TURBT must be within 60 days of registration. There is no 
requirement for muscularis propria in the specimen of Ta/CIS patients, but the 
tissue from the first and second TURBTs must be submitted for central review. If a 
patient with Ta/T1 disease undergoes repeat TURBT, the patient will be stratified 
as having CIS if there is CIS on either TURBT. 
 
g. 
Patients must not have had urothelial carcinoma in the prostatic urethra within the 
previous 24 months or muscle invasive urothelial carcinoma of the bladder at any 
time. Patients with prior urothelial carcinoma in the upper urinary tract within the 
previous 24 months will only be eligible if they had ≤ T1 carcinoma and were 
treated with nephroureterectomy. Patients must have a CT or MRI (including CT-


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IVP, CT-urogram or MR-urogram) of the abdomen and pelvis to rule out upper tract 
malignancy and intra-abdominal metastases within 90 days prior to registration. If 
a patient cannot tolerate intravenous contrast, a retrograde pyelogram should be 
performed within 90 days prior to registration. 
 
h. 
Patients must be deemed unfit for radical cystectomy by the treating physician, or 
the patient must refuse radical cystectomy, which is considered standard of care 
for these patients. The reason for patients not to undergo cystectomy will be clearly 
documented. 
 
5.3 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must be BCG-unresponsive.  A patient is BCG-unresponsive if they meet 
one or more of the following criteria: 
 
• 
Patient has persistent or recurrent high-grade Ta/CIS urothelial 
carcinoma after completing therapy with at least induction BCG (≥ 5 
doses) and first round maintenance (≥ 2 doses) or second induction 
BCG (≥ 2 doses). Both rounds of BCG must have been administered 
within a 12 month period. These patients must have either had high-
grade Ta tumors and did not achieve a disease-free state for more 
than 6 months following last dose of BCG, or they had CIS and did not 
achieve a CR. S1605 registration must occur within 9 months of the 
last dose of BCG. 
o 
If a patient does not meet these criteria only because the last 
dose of BCG was more than 9 months ago, the patient may 
become eligible if he/she shows histologically proven high-
grade recurrence after an additional round of induction or 
maintenance BCG (≥ 3 doses) within 9 months prior to 
registration. 
• 
Patient has persistent or recurrent high grade T1 urothelial carcinoma 
after completing therapy with at least induction BCG (≥ 5 doses). 
Patients with recurrent high grade T1 urothelial carcinoma after 
additional rounds of BCG will also be eligible, but one round of 
maintenance therapy or a second induction is not a pre-requisite for 
these patients. Trial registration must occur within 9 months of the last 
dose of BCG. 
 
o 
If a patient does not meet these criteria only because the last dose 
of BCG was more than 9 months ago, the patient may become 
eligible if he/she shows histologically proven high grade 
recurrence after an additional round of induction or maintenance 
BCG (≥ 3 doses) within 9 months prior to registration. 
• 
Patient achieves disease-free state at 6 month time point (i.e., 
complete response; presence of only low-grade tumor at this timepoint 
is still considered complete response) after induction and 
maintenance (or second round of induction) BCG but later 
experiences a high-grade Ta/T1recurrence (with or without 
concomitant CIS) within 6 months after the last dose of BCG or 
recurrent CIS (in absence of concomitant Ta/T1 tumor) within 12 
months after the last BCG dose. The time of eligibility is measured 
from the last dose of BCG to the time of disease recurrence. The 
patient must be registered on the trial within 60 days of this recurrence, 
or within 60 days of a re-TURBT if indicated. See Section 5.2f for 
TURBT requirements.  
 
b. 
All adverse events associated with any prior surgery and intravesical therapy must 
have resolved to Grade ≤ 2 prior to registration. 


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c. 
Patients must not have had prior systemic chemotherapy for bladder cancer or 
systemic immunotherapy, including, but not limited to interferon alfa-2b, high dose 
IL-2, PEG-IFN, anti-PD-1, anti-PD-L1, intra-tumoral. Patients must not have had 
vaccine therapies within 6 weeks prior to registration. Patients must not have 
received or be planning to receive any of the prohibited therapies listed in Section 
7.3 during protocol treatment. Prior intravesical administration of chemotherapy, 
interferon, Vicinium™ (VB4-845), BC-819 or Instiladrin™ (rAd-interferon-
alpha/Syn3) is allowed if all other criteria are met and the last administration was 
≥ 30 days before registration. 
 
d. 
Patients must not be planning to receive concomitant other biologic therapy, 
radiation therapy, intravesical chemotherapy, surgery, or other anti-cancer therapy 
while on this protocol. 
 
e. 
Patients must not have received any prior radiation to the bladder for bladder 
cancer. 
 
f. 
Patients must not have received treatment with systemic immunosuppressive 
medications (including, but not limited to, prednisone, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] 
agents) within 4 weeks prior to registration.  Exceptions: (1) Patients may have 
received acute, low dose, systemic immunosuppressant medications (e.g., a one-
time dose of dexamethasone for nausea); (2) The use of inhaled corticosteroids 
and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed. 
 
g. 
Patients must not have received a live, attenuated vaccine within 4 weeks before 
registration or anticipation that such a live, attenuated vaccine will be required 
during the study and up to 5 months after the last dose of atezolizumab. 
 
• 
Influenza vaccination should be given during influenza season only 
(approximately October to March).  Patients must not receive live, 
attenuated influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at 
any time during the study. 
 
h. 
Patients must not require treatment with a RANKL inhibitor (e.g. denosumab) who 
cannot discontinue it before treatment with atezolizumab. 
 
5.4 
Clinical/Laboratory Criteria 
 
a. 
Patients must be ≥ 18 years of age. 
 
b. 
Patients must have adequate bone marrow function as evidenced by all of the 
following: ANC ≥ 1,500/ microliter (mcL); platelets ≥ 100,000/mcL; Hemoglobin ≥ 
9 g/dL. These results must be obtained within 42 days prior to registration. 
 
c. 
Patients must have adequate hepatic function as evidenced by the following: total 
bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except Gilbert’s 
Syndrome, who must have a total bilirubin < 3.0 mg/dL), and AST or ALT ≤ 2 x 
IULN. These results must be obtained within 42 days prior to registration. 
 
d. 
Patients must have adequate renal function as evidenced by ONE of the following: 
serum creatinine ≤ 1.5 ULN OR measured or calculated creatinine clearance ≥ 30 
mL/min. This result must have been obtained within 42 days prior to registration. 
 
Estimated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
 
72 x creatinine (mg/dl) 


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e. 
Patients must have Zubrod Performance Status ≤ 2 (see Section 10.11). 
 
f. 
Patients must have a baseline ECG performed within 42 days prior to registration. 
 
g. 
Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis 
(including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, 
cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis. 
 
h. 
Patients must not have an active infection requiring oral or IV antibiotics within 14 
days prior to registration. Patients receiving prophylactic antibiotics (e.g., for 
prevention of a urinary tract infection or chronic obstructive pulmonary disease) 
are eligible. 
 
i. 
Patients must not have severe infections within 28 days prior to registration, 
including but not limited to hospitalization for complications of infection, 
bacteremia, or severe pneumonia. 
 
j. 
Patients must not have active autoimmune disease that has required systemic 
treatment in past two years (i.e., with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
Autoimmune diseases include, but are not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis 
associated 
with 
antiphospholipid 
syndrome, 
Wegener’s 
granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, 
multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. 
 
k. 
Patients must not have undergone prior allogeneic bone marrow transplantation or 
prior solid organ transplantation. 
 
l. 
Patient must not have active tuberculosis. 
 
m. 
Patients must not have active hepatitis B (chronic or acute) or active hepatitis C 
infection. 
• 
Patients with past or resolved hepatitis B infection (defined as having a 
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc 
[antibody to hepatitis B core antigen] antibody test) are eligible. 
• 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA. 
 
n. 
Patients positive for HIV are eligible only if they have all of the following: 
a) A stable regimen of highly active anti-retroviral therapy (HAART) 
b) No requirement for concurrent antibiotics or antifungal agents for the 
prevention of opportunistic infections 
c) A CD4 count above 250 cells/mcL and an undetectable HIV viral load on 
standard PCR-based tests. 
 
o. 
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 
Stage I or II cancer from which the patient is currently in complete remission, or 
any other cancer from which the patient has been disease free for five years. 
 
p. 
Patients must not be pregnant or nursing due to the potential teratogenic side 
effects of the protocol treatment. Administration of atezolizumab may have an 
adverse effect on pregnancy and poses a risk to the human fetus, including 
embryo-lethality.  Women of child-bearing potential and men must agree to use 


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adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry, for the duration of study participation, and for 5 months (150 
days) after the last dose of study agent. A woman is considered to be of 
“reproductive potential” if she has had a menses at any time in the preceding 12 
consecutive months.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform 
her treating physician immediately. 
 
q. 
Due to the potential drug reaction with atezolizumab, patients must not be known 
to be allergic to Chinese hamster egg or ovaries. 
 
5.5 
Specimen Submission Criteria 
 
a. 
Patients must be offered the opportunity to participate in specimen banking for 
future studies, to include translational medicine studies as outlined in Section 15.0. 
 
5.6 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.3 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
 
6.0 
STRATIFICATION FACTORS 
 
CIS: Present vs. Absent (i.e., Ta/T1 only) 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Parminder Singh at 
(singh.parminder@mayo.edu) or Dr. Peter Black at (pblack@mail.ubc.ca). For dosing principles or 
questions, please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" 
at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf.  
 
7.1 
Pre-Medication 
 
Premedication is not permitted for the first dose of atezolizumab.  Premedication with 
antihistamines or antipyretics/analgesics (e.g., acetaminophen) may be administered for 
subsequent infusions at the discretion of the treating physician.  See Section 7.2 for the 
management of Infusion Related Reactions. 
 
7.2 
Treatment 
 
Patients will receive intravenous atezolizumab (1200 mg) once every 21 days for a total of 
17 doses (cycles).  Atezolizumab treatment may be administered up to three days before 
or after the protocol-specified dose administration date, each 21 day cycle, due to 
administrative reasons.  Atezolizumab treatment will be administered on an outpatient basis.   
 
Agent 
Dose 
Route 
Days 
Interval 
Notes 
 
Atezolizumab 
1200 mg 
Intravenous 
1 
q 21 days for a maximum of 
 
 
over 60 minutes 
 
 
17 cycles 


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(51 weeks) 
 
 
Atezolizumab administration instructions: 
 
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
 
Atezolizumab is administered as an intravenous infusion over 60 minutes. If the first 
infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Do not 
administer atezolizumab as an intravenous push or bolus.  Vital signs (heart rate, 
respiratory rate, blood pressure, and temperature) should be monitored at the following 
timepoints during drug infusion:  
 
• 
Before:  Within 60 minutes of starting 
• 
During:  15- 30 minutes after start 
• 
After: At the end of infusion, within 30 minutes 
 
No premedication is indicated for administration of Cycle 1 of atezolizumab. Patients who 
experience an infusion related reaction with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g. acetaminophen) for 
subsequent infusions. 
 
Premedication is not permitted for the first dose of atezolizumab.  Premedication with 
antihistamines or antipyretics/analgesics (e.g., acetaminophen) may be administered for 
subsequent infusions at the discretion of the treating physician.  The management of 
Infusion Related Reactions will be according to severity as follows: 
 
• 
In the event that a patient experiences a Grade 1 Infusion Related Reaction during 
Cycle 1, the infusion rate should be reduced to half the rate being given at the time 
of event onset.  Once the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.  If tolerated, the 
infusion rate may then be increased to the original rate. 
• 
In the event that a patient experiences a Grade 2 Infusion Related Reaction, or 
flushing, fever, or throat pain, the infusion should be immediately interrupted and 
the patient should receive aggressive symptomatic treatment.  The infusion should 
be restarted only after the symptoms have adequately resolved to baseline grade.  
The infusion rate at restart should be half of the infusion rate that was in progress 
at the time of the onset of the Infusion Related Reaction.  For subsequent infusions, 
administer oral premedication with antihistamine and anti-pyretic and monitor 
closely for Infusion Related Reactions 
• 
For Grade 3 or 4, Infusion Related Reactions, the infusion should be stopped 
immediately, and aggressive resuscitation and supportive measures should be 
initiated (e.g., oral or IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).  Atezolizumab should be permanently discontinued.  
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event; retreatment 
requires consultation with the Study Chair. 
 
 


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For anaphylaxis precautions, use the following procedure: 
 
Equipment Needed 
 
• 
Tourniquet 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in 
accordance with standard practice  
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
Procedures 
 
 
In the event of a suspected anaphylactic reaction during atezolizumab infusion, 
the following procedures should be performed: 
 
• 
Stop the study drug infusion. 
• 
Apply a tourniquet proximal to the injection site to slow systemic absorption 
of study drug.  Do not obstruct arterial flow in the limb. 
• 
Maintain an adequate airway. 
• 
Administer antihistamines, epinephrine, or other medications as required by 
patient status and directed by the physician in charge. 
• 
Continue to observe the patient and document observation. 
 
7.3 
Disease Assessment 
 
See Section 9.0 for disease assessment time points (approximately every 12 weeks).  
Disease assessment timing (cystoscopy, urine cytology, and biopsy) is to be based on 
calendar timing counted as weeks after registration, not based on cycles or drug 
administration. 
 
Week 13: 
 
Office cystoscopy and urine cytology will be performed 13 weeks after registration.  
Patients with suspicious cystoscopy or cytology findings positive for malignancy at 13 
weeks (or at any other disease assessment time point) must undergo further evaluation 
with TURBT/biopsy, and patients with high-grade T1 or higher stage recurrences will be 
taken off protocol treatment.  Persistent Ta or CIS at 13 weeks and low-grade recurrences 
at any timepoint will be tolerated without treatment interruption.   
 
Only frankly malignant cytology (equivalent to Papanicolaou class V) will be considered 
“positive” and used to determine the need for bladder biopsy and further evaluation. 
Cytology is limited by its subjectivity and poor reproducibility so that lower grades of 
possible cytologic abnormalities cannot be used reliably. All patients will undergo close 
monitoring of the urine cytology, so that adverse changes will be noted promptly. 
Week 25: 
 
Complete response for patients with CIS component will be assessed with urine cytology, 
cystoscopy, and mandatory bladder biopsy at Week 25 (within ± 7 days of the start of 
Week 25, regardless of treatment delays).  If patient is found to have persistent CIS or 
other high-grade disease, patient will be removed from protocol treatment.  Patients with 
CIS at study entry achieving a complete response at 25 weeks will continue on protocol 
therapy as planned. 
 
CIS patients with suspicious cystoscopy findings or cytology positive for malignancy at 
Week 13 and a negative biopsy at Week 13 are not required to undergo the mandatory 
Week 25 biopsy if their Week 25 cystoscopy is not suspicious and Week 25 cytology is 
negative for malignancy. A patient with positive cytology but negative biopsy at Week 25 


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must have re-evaluation of the upper tracts via CT or MRI (including CT-IVP, CT-urogram 
or MR-urogram) of the abdomen and pelvis (males and females) and biopsy of the prostatic 
urethra (males only). 
 
Patients without CIS component at study entry (Ta/T1 only) will be assessed with cytology 
and cystoscopy. Patients with suspicious cystoscopy or cytology findings positive for 
malignancy at 25 weeks (or at any other disease assessment time point) must undergo 
further evaluation with TURBT/biopsy, and patients with any high-grade (Ta/T1/CIS) or 
higher stage recurrences will be taken off protocol treatment. Low-grade recurrences at 
any time point will be tolerated without treatment interruption. 
 
Subsequent Disease Assessments:  
 
For all patients, cystoscopic and cytologic monitoring will continue every 3 months for the 
first two years, then every six months for Years 3-5 until high-grade recurrence. Patients 
with suspicious cystoscopy or cytology findings positive for malignancy must undergo 
further evaluation with TURBT/biopsy. 
 
Patients without evidence of a high-grade recurrence by 18 months (week 73) are required 
to have a CT or MRI at 18 months (week 73). 
 
7.4 
Prohibited and Cautionary Medications 
 
Patients are prohibited from receiving the following therapies during the screening and 
treatment phases of this trial: 
• 
Anti-cancer systemic chemotherapy or biological therapy. 
• 
Immunotherapy not specified in this protocol. 
▪ 
No systemic or intravesical use of any non-study anti-cancer agent (investigational or 
non-investigational). 
• 
Investigational agents other than atezolizumab. 
• 
Radiation therapy 
• 
Live vaccines: Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, 
and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. 
Flu-Mist®) are live attenuated vaccines, and are not allowed. Prior administration of 
intravesical BCG is allowed. 
• 
Glucocorticoids for any purpose other than to modulate symptoms from an event of 
suspected immunologic etiology. The use of physiologic doses of corticosteroids 
(defined as 10 mg prednisone) are acceptable, however site investigators should 
consult with the Study Chair for any dose higher than 10 mg prednisone. 
 
7.5 
Criteria for Removal from Protocol Treatment 
 
a. 
High Grade T1 or greater at Week 13 or later 
 
b. 
Recurrence of high-grade disease, muscle invasive or metastatic disease, or high-
grade upper tract or urethral involvement (as defined in Section 10.0) at Week 25 
or later. 
 
c. 
Persistent CIS at Week 25 biopsy. 
 
d. 
Unacceptable toxicity 
 
e. 
Treatment delay > 84 consecutive days for any reason, except as specified in 
Section 8.0. 
 
f. 
Completion of protocol treatment. 
 


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g. 
Pregnancy 
 
h. 
The patient may withdraw from the study at any time for any reason. 
 
i. 
The investigator may discontinue treatment if they determine that the patient’s 
continued treatment on the study is detrimental to their long-term health, or due 
to poor compliance with the study’s required visits and treatments. 
 
7.6 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.7 
Follow-Up Period 
 
All patients will be followed for recurrence, progression, and survival for 5 years after 
registration. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting  
  
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only. The CTCAE Version 5.0 can be 
downloaded from the CTEP home page (https://ctep.cancer.gov) All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting. A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov). All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0. 
 
8.2 
General Adverse Event Management and Dose Modification Guidelines 
 
Patients may temporarily suspend study treatment for up to 84 days (12 weeks) beyond 
the scheduled date of delayed infusion if study drug-related toxicity requiring dose 
suspension is experienced.  If atezolizumab is held because of AEs for 84 days beyond 
the scheduled date of infusion, the patient will be discontinued from atezolizumab and will 
be followed for safety and efficacy as specified in this protocol.  If the AE resolves within 
84 days and the patient is receiving corticosteroid therapy for the event, atezolizumab may 
be held for longer than 84 days (up to 4 additional weeks) in order to allow tapering of the 
steroid dose to ≤10 mg oral prednisone or equivalent. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be 
allowed.  The acceptable length of interruption will be at the discretion of the Study Chair. 
 
 


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Atezolizumab must be permanently discontinued if the patient experiences any of the 
following events, regardless of benefit: 
 
• 
Grade 4 pneumonitis 
• 
AST or ALT >5×ULN or total bilirubin >3×ULN  
• 
Grade 4 diarrhea or colitis 
• 
Grade 4 hypophysitis 
• 
Any 
grade 
myasthenic 
syndrome/myasthenia 
gravis, 
Guillain-Barré 
or 
meningoencephalitis 
• 
Grade 4 ocular inflammatory toxicity 
• 
Grade 4 pancreatitis or any grade of recurrent pancreatitis 
• 
Grade 4 rash 
• 
Any grade myocarditis 
• 
Grade 3 or 4 nephritis 
 
Treatment may, under limited and compelling circumstances, be resumed in patients who 
have recovered from the following events, but only after consultation with the Study Chair: 
 
• 
Grade 3 pneumonitis 
• 
Grade 3 ocular inflammatory toxicity 
• 
Grade 3 or 4 infusion-related reactions 
 
Any toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, may be used to determine a possible immunogenic etiology.  
Although most immune-related adverse events (irAEs) observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications (Di Giacomo et al., 2010).  
Discontinuation of atezolizumab may not have an immediate therapeutic effect, and there 
is no available antidote for atezolizumab.  In severe cases, immune-related toxicities may 
be acutely managed with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.  The investigator should consider the benefit-risk balance 
prior to further administration of atezolizumab.   
 
For detailed information regarding management of adverse events associated with 
atezolizumab, please refer to the most current version of the Atezolizumab Investigator’s 
Brochure and the FDA product label. 
 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care with 
continued treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be 
withheld and oral and/or parenteral steroids administered.  Recurrent Grade 2 irAEs may 
also mandate withholding atezolizumab or the use of steroids.  Assessment of the 
benefit-risk balance should be made by the investigator, with consideration of the totality 
of information as it pertains to the nature of the toxicity and the degree of clinical benefit a 
given patient may be experiencing prior to further administration of atezolizumab.  
Atezolizumab should be permanently discontinued in patients with life-threatening irAEs. 
 
Patients should be assessed clinically (including review of laboratory values) for toxicity 
prior to, during, and after each infusion.  If unmanageable toxicity due to atezolizumab 
occurs at any time during the study, treatment with atezolizumab should be discontinued. 
 
Systemic Immune Activation 
Systemic immune activation is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the following: 


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• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D-dimer 
• 
Ferritin 
• 
Triglycerides 
• 
AST, ALT, and total bilirubin 
• 
LDH 
• 
Complete 
neurologic 
and 
abdominal 
examination 
(assess 
for 
hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the Study 
Chair for additional recommendations. 
 
8.3 
Management of Specific AEs 
 
Management of certain AEs of concern, including immune-related pneumonitis, hepatitis, 
colitis, endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and potential 
ocular toxicities are presented in the Atezolizumab Investigator’s Brochure.  See Section 
7.2 for guidelines for the management of Infusion Related Reactions and Anaphylaxis. 
 
Pulmonary events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study. 
 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in the table 
below. 
 
Endocrine disorders 
Patients experiencing one or more unexplained AEs possibly indicative of endocrine 
dysfunction (including fatigue, myalgias, impotence, mental status changes, and 
constipation) should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies.  The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) and free T3 and T4 
levels should be obtained to determine whether thyroid abnormalities are present.  TSH, 
prolactin, and a morning cortisol level will help to differentiate primary adrenal insufficiency 
from primary pituitary insufficiency.  The table below describes dose management 
guidelines for hyperthyroidism, hypothyroidism, symptomatic adrenal insufficiency, and 
hyperglycemia. 
 
Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration 
of atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but 
not limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or electrolyte 
imbalances needs to be distinguished from potential meningoencephalitis resulting from 
infection (bacterial, viral, or fungal) or progression of malignancy, or secondary to a 
paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently evaluated with a 
CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  
If deemed safe by the treating physician, a lumbar puncture should be performed and a 
neurologist should be consulted. 
 


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Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines. 
 
Neurologic disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies. 
 
The table below presents management and dose modification guidelines for specific AEs.  
For recommendations to hold atezolizumab and begin corticosteroid treatment, use the 
following guidance for tapering the corticosteroid and resuming atezolizumab therapy after 
resolution of the event: 
 
• 
Corticosteroids must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
• 
Atezolizumab may be held for a period of time beyond 12 weeks (up to 4 additional 
weeks) to allow for corticosteroids to be reduced to 10 mg/day oral prednisone or 
equivalent. 
 
AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Abdominal pain 
Acute 
abdominal pain 
Symptoms of abdominal pain associated with 
elevations of amylase and lipase, suggestive 
of pancreatitis, have been associated with 
administration of other immunomodulatory 
agents.  The differential diagnosis of acute 
abdominal pain should include pancreatitis.  
Appropriate workup should include an 
evaluation for obstruction, as well as serum 
amylase and lipase tests.  See the guidelines 
for “Amylase and/or lipase increase” and 
“Immune-related pancreatitis” elsewhere in 
this table, as needed. 
 
Right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should be 
evaluated for potential hepatotoxicity (see the 
“Hepatotoxicity” guideline elsewhere in this 
table). 
Adrenal 
insufficiency 
Grade 2+ 
(symptomatic) 
Hold atezolizumab. 
 
Refer patient to endocrinologist. 
 
Perform appropriate imaging. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If event resolves to Grade 1 or better and 
patient is stable on replacement therapy (if 
required) within 12 weeks, taper 
corticosteroids and resume atezolizumab 
according to the guidelines above. 
 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better or 
patient is not stable on replacement therapy 
within 12 weeks. 
Amylase and/or 
lipase increased 
Grade 1 
Continue atezolizumab. 
 
Monitor amylase and lipase prior to dosing. 
Grade 2 
Continue atezolizumab. 
 
Monitor amylase and lipase weekly. 
 
For prolonged elevation (e.g., 3 weeks), 
consider treatment with 10 mg/day oral 
prednisone or equivalent. 
Grade 3 or 4 
Hold atezolizumab. 
 
Refer patient to gastrointestinal (GI) specialist. 
 
Monitor amylase and lipase every other day. 
 
If no improvement, consider treatment with 
1−2 mg/kg/day oral prednisone or equivalent. 
 
If event resolves to Grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines 
above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks. 
 
For recurrent events, permanently discontinue 
atezolizumab.  
Dermatologic 
toxicity/rash (e.g., 
maculopapular or 
purpura) 
Grade 1 
Continue atezolizumab. 
 
Consider topical steroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Grade 2 
Continue atezolizumab.  Consider 
dermatologist referral. 
 
Administer topical corticosteroids. 
 
Consider higher potency topical corticosteroids 
if event does not improve. 
Grade 3 
Hold atezolizumab.   
 
Refer patient to dermatologist.  Administer oral 
prednisone 10 mg or equivalent.  If the event 
does not improve within 48−72 hours, increase 
dose to1–2 mg/kg/day or equivalent. 
Restart atezolizumab if event resolves to 
Grade 1 or better within 12 weeks. 
 
Permanently discontinue atezolizumab if event 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
does not resolve to Grade 1 or better within 12 
weeks. 
Grade 4 
Permanently discontinue atezolizumab.  
Patient may not resume treatment, regardless 
of benefit.  Otherwise, manage as above. 
Persistent 
and/or severe 
rash or pruritus, 
any grade 
A dermatologist should evaluate the event.  A 
biopsy should be performed unless 
contraindicated. 
Diarrhea or colitis 
Any grade 
Patients should be advised to inform the 
investigator if any diarrhea occurs, even if it is 
mild. 
 
All events of diarrhea or colitis should be 
thoroughly evaluated for other more common 
etiologies.  For events of significant duration or 
magnitude or associated with signs of 
systemic inflammation or acute-phase 
reactants (e.g., increased CRP, platelet count, 
or bandemia):  Perform sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic 
biopsy, with three to five specimens for 
standard paraffin block to check for 
inflammation and lymphocytic infiltrates to 
confirm colitis diagnosis. 
 
Grade 1 
Continue atezolizumab. 
 
Initiate symptomatic treatment. 
 
Endoscopy is recommended if symptoms 
persist for 7 days. 
 
Monitor closely. 
 
Grade 2 
Hold atezolizumab. 
 
Initiate symptomatic treatment. 
 
Patient referral to GI specialist is 
recommended. 
 
For recurrent events or events that persist >5 
days, initiate treatment with 1−2 mg/kg/day 
oral prednisone or equivalent.  
 
If event resolves to Grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines 
above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks.  Resumption of atezolizumab may be 
considered, after consultation with the trial PI, 
in patients who are deriving benefit and have 
fully recovered from the immune-related event. 
 
Grade 3 
Hold atezolizumab. 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
 
Refer patient to GI specialist for evaluation 
and confirmatory biopsy. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If event resolves to Grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines 
above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks.  Resumption of atezolizumab may be 
considered, after consultation with the Study 
Chair, in patients who are deriving benefit and 
have fully recovered from the immune-related 
event. 
 
Grade 4  
Permanently discontinue atezolizumab. 
Patient may not resume treatment, regardless 
of benefit. 
 
Refer patient to GI specialist for evaluation 
and confirmation biopsy. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month.  
Hepatotoxicity  
Right upper-
quadrant 
abdominal pain 
and/or 
unexplained 
nausea or 
vomiting 
Risk of immune-mediated hepatitis.  LFTs 
should be performed immediately, and LFTs 
should be reviewed before administration of 
the next dose of study drug.  For patients with 
elevated LFTs, concurrent medication, viral 
hepatitis, and toxic or neoplastic etiologies 
should be considered and addressed, 
as appropriate. 
 
Symptoms of abdominal pain associated with 
elevations of amylase and lipase, suggestive 
of pancreatitis, have been associated with the 
administration of atezolizumab.  The 
differential diagnosis of acute abdominal pain 
should also include pancreatitis, as described 
below. 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Grade 1 
hepatic event 
Continue atezolizumab. 
 
Monitor LFTs until values resolve to within 
normal limits. 
Grade 2 
hepatic event, 
≤5 days 
Continue atezolizumab. 
 
Monitor LFTs more frequently until values 
resolve to baseline values. 
Grade 2 
hepatic event, 
>5 days 
Hold atezolizumab. 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to Grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines 
above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks. 
Grade 3 or 4 
hepatic event 
Permanently discontinue atezolizumab. 
 
Consider patient referral to GI specialist for 
evaluation and liver biopsy to establish 
etiology of hepatic injury.  
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. 
Hyperglycemia 
Grade 1 or 2 
Continue atezolizumab. 
 
Initiate treatment with insulin if needed. 
 
Monitor for glucose control. 
 
Grade 3 or 4 
Hold atezolizumab. 
 
Initiate treatment with insulin. 
 
Monitor for glucose control. 
Resume atezolizumab when symptoms 
resolve and glucose levels are stable. 
 
Hyperthyroidism 
Grade 1 
(asymptomatic) 
TSH  0.1 mU/L and  0.5 mU/L: 
Continue atezolizumab.  Monitor TSH 
every 4 weeks. 
 
TSH  0.1 mU/L: 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Follow guidelines for symptomatic 
hyperthyroidism. 
 
Grade 2+ 
(symptomatic) 
Hold atezolizumab. 
 
Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
 
Consider patient referral to endocrinologist. 
 
Resume atezolizumab when symptoms are 
controlled and thyroid function is improving. 
 
Permanently discontinue atezolizumab for 
life-threatening immune-related 
hyperthyroidism. 
Hypothyroidism 
Grade 1 
(asymptomatic) 
Continue atezolizumab.   
 
Start thyroid-replacement hormone.   
 
Monitor TSH weekly. 
Grades 2+ 
(symptomatic) 
Hold atezolizumab.   
 
Start thyroid-replacement hormone.  Consider 
referral to an endocrinologist.  
 
Monitor TSH weekly. 
 
Restart atezolizumab when symptoms are 
controlled and thyroid function is improving.  
Meningo-
encepahlitis, 
immune-related 
 
(signs and 
symptoms in 
absence of an 
identified alternate 
etiology) 
 
All grades 
Permanently discontinue atezolizumab. 
Patient may not resume treatment, regardless 
of benefit. 
 
Refer patient to neurologist. 
 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert 
to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Myasthenia gravis 
and Guillain-Barré 
syndrome 
All grades 
Permanently discontinue atezolizumab. 
Patient may not resume treatment, regardless 
of benefit. 
 
Refer patient to neurologist. 
 
Initiate treatment as per institutional 
guidelines. 
 
Consider initiation of 1−2 mg/kg/day oral or IV 
prednisone or equivalent. 
Myocarditis 
All grades 
Permanently discontinue atezolizumab. 
Patient may not resume treatment, regardless 
of benefit. 
Neuropathy, 
immune-related 
 
(sensory and/or 
motor) 
Grade 1 
Continue atezolizumab. 
 
 
Evaluate for alternative etiologies. 
 
Grade 2 
Hold atezolizumab. 
 
Evaluate for alternative etiologies. 
 
Initiate treatment as per institutional 
guidelines. 
 
Resume atezolizumab if event resolves to 
Grade 1 or better within 12 weeks. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks. 
 
Grade 3 or 4 
Permanently discontinue atezolizumab. 
 
Initiate treatment as per institutional 
guidelines. 
Ocular event (e.g., 
uveitis, retinal 
events) 
Grade 1 
Continue atezolizumab. 
 
Patient referral to ophthalmologist is strongly 
recommended. 
 
Initiate treatment with topical corticosteroid 
eye drops and topical immunosuppressive 
therapy. 
 
If symptoms persist, treat as a Grade 2 event. 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Grade 2 
Withhold atezolizumab. 
 
Patient referral to ophthalmologist is strongly 
recommended. 
 
Initiate treatment with topical corticosteroid 
eye drops and topical immunosuppressive 
therapy 
If event resolves to Grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines 
above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 
12 weeks. 
Grade 3 or 4 
Permanently discontinue atezolizumab.   
 
Refer patient to ophthalmologist. 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. For Grade 3 
AEs, patient may only resume treatment after 
consultation with the trial PI; for Grade 4, 
patient cannot resume treatment, regardless of 
benefit. 
Pancreatitis, 
immune related 
Grade 2 or 3 
Hold atezolizumab. 
 
Refer patient to GI specialist. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If event resolves to Grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines 
above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 
12 weeks.  Patient may only resume treatment 
after consultation with the trial PI. 
 
For recurrent events, permanently discontinue 
atezolizumab.  Patient may not resume 
treatment, regardless of benefit. 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Grade 4 
Permanently discontinue atezolizumab. 
Patient may not resume treatment, regardless 
of benefit. 
 
Refer patient to GI specialist. 
 
Initiate treatment with 1−2 mg/kg/day 
intravenous methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. 
Pulmonary toxicity 
All pulmonary 
events 
Evaluate thoroughly for other commonly 
reported etiologies such as 
pneumonia/infection, lymphangitic 
carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease 
(COPD), or pulmonary hypertension. 
Grade 1 
Continue atezolizumab and monitor closely.   
 
Re-evaluate on serial imaging. 
 
Consider patient referral to a pulmonary 
specialist. 
 
For recurrent pneumonitis, treat as a Grade 3 
or 4 event. 
Grade 2 
Hold atezolizumab.   
 
Refer patient to pulmonary and infectious 
disease specialists and consider 
bronchoscopy or bronchoscopic alveolar 
lavage (BAL). 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to Grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines 
above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 
12 weeks. 
 
For recurrent events, treat as a Grade 3 or 4 
event. 


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AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
Grade 3 or 4 
Hold atezolizumab. 
 
Bronchoscopy or BAL is recommended. 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month.  For Grade 3 
AEs, patient may only resume treatment after 
consultation with the Study Chair; for Grade 4, 
patient cannot resume treatment, regardless of 
benefit. 
 
8.4 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Parminder Singh at 
917/816-8595 (singh.parminder@mayo.edu) or Dr. Peter Black at 605/875-4301 
(pblack@interchange.ubc.ca).  
 
8.5 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 


S1605 
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9.0 
STUDY CALENDAR 
 
9.1 
TREATMENT AND SPECIMEN SUBMISSION 
REQUIRED 
STUDIES 
Base
-line 
WEEK 
Off Tx 
Prior to 
HG 
Recur 
≠ 
After 
HG 
Recur 
# 
1 4 
7 
10 
13 * 
16 
19 
22 
25* 
28 
31 
34 
37 
40 
43 
46 
49 
61 
73 
85 
97 
109+ 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and 
Physical 
Exam 
X Ʃ 
  
x 
x 
X 
x 
x 
x 
x 
x 
x 
  
x 
  
x 
  
x  
  
  
  
  
  
  
  
  
Weight and 
Perfor-
mance 
Status 
X Ʃ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Toxicity 
Notation Ω 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ω 
  
  
  
  
X Ω 
X Ω 
Baseline 
Abnorma-
lities 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Assess 
pulmonary 
signs and 
symptoms α 
  
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ω 
  
  
  
  
X Ω 
X Ω 
Disease 
Assessment 
≠ 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X  
q24 
wks 
X 
 
LABORA-
TORY 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CMP/ 
Serum 
Chemistry € 
X λ 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
CBC w/ diff, 
platelets β 
X λ 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
Pregnancy 
test (if 
applicable) § 
X λ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TSH ¥ 
X λ 
  
  
x 
  
X 
  
x 
  
X 
  
x 
  
X 
  
x 
  
X 
  
  
  
  
  
  
  
Cal 9.1 continued on next page. Click here for Footnotes: 
 
 


S1605 
Page 42 
Version Date 09/20/2021 
 
 
 
 
REQUIRED 
STUDIES 
Base
-line 
WEEK 
Off Tx 
Prior to 
HG 
Recur 
≠ 
After 
HG 
Recur 
# 
1 
4 
7 
10 
13 * 
16 
19 
22 
25* 
28 
31 
34 
37 
40 
43 
46 
49 
61 
73 
85 
97 
109+ 
 
 
PROCE-
DURES 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Bladder 
Biopsy  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cystoscopy 
≠ 
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X  
q24 
wks 
X 
  
Urine 
Cytology  
≠ § 
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X  
q24 
wks 
X 
  
X-RAYS 
AND 
SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CT or MRI 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
¿ 
  
  
  
  
  
TREATME
NT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Atezoli-
zumab α 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
SPECIMEN 
SUB-
MISSION 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Slides for 
Pathology 
Review 
(required) Δ 
X Ѳ 
  
  
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X  
FFPE 
tissue from 
TURBT/bio
psy π 
X 
  
  
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
Whole 
Blood £ 
X 
X 
X  X 
  
X 
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
Urine  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
X 
  
 X 
  
  
  
  
  
Urine 
Cytology 
Slide 
  
 
 
  
  
X Ѱ 
  
  
  
X Ѱ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Click here for Footnotes: 
 


S1605 
Page 43 
Version Date 09/20/2021 
 
 
 
 
Footnotes for 9.1 
* If no treatment delays, treatment Cycles 5, 9, 13 and 17 coincide with disease assessment timepoints.  
€  Bilirubin, SGOT [AST] or SGPT [ALT], creatinine, glucose, calcium, sodium, potassium, chloride and bicarbonate  
β  ANC, platelets, hemoglobin 
£ Collect whole blood prior to drug infusion. See protocol Section 15.0 for details.   
Δ  Three H&E stained slides are REQUIRED to be submitted for central pathology review at any time a biopsy is performed for suspected recurrence.  
See protocol Section 12.0 for details and shipping instructions. 
α Atezolizumab is given every 21 days. Vital signs should be monitored before, during, and after infusion. See Section 7.2 for details. 
Ʃ To be performed within two weeks prior to registration  
¥ To be performed more frequently if clinically indicated.  
≠  Disease assessment will be performed every 3 months (12 weeks) for the first 2 years, then every 6 months (24 weeks) for Years 3-5 until HG 
recurrence or death. Disease assessment includes office cystoscopy and cytology A biopsy is required for suspicious cystoscopy findings or 
cytology results positive for malignancy.  
# Following a HIGH-GRADE recurrence within 5 years after registration, disease assessment is at discretion of treating investigator and the S1605 
Disease Assessment Form does not need to be submitted. However, the S1605 Follow-up Form is still required for the full 5 year duration or 
death. 
  Bladder biopsy is REQUIRED for patients with any component of CIS at study entry (with or without concomitant Ta/T1 disease) within 7 days of 
Week 25 after registration, except where noted in Section 7.3. All patients with suspicious cystoscopy findings or cytology positive for malignancy 
at any of the indicated diseases assessment times (or any other time, i.e. for cause) will undergo biopsy or TURBT. Patient should continue 
receiving atezolizumab while waiting for biopsy. Submit Pathology report for all biopsies performed, regardless of result.  
π  Submit FFPE tissue any time a biopsy is performed for suspected recurrence of any type or persistent CIS. 
¿  The CT or MRI scan must be performed at Week 73 for all patients who have not had a HG recurrence before that timepoint and scans must be 
submitted via AG Mednet. See Section 15.2 for instructions. 
§ Submit all cytology reports as a RAVE source document. 
 Follow-up safety assessments are required at 30 days and 90 days after the last dose of atezolizumab, regardless if patient has started a new 
cancer therapy. Report ALL toxicities, ALL Grades for first 30 days following last dose of protocol treatment on the last S1605 Adverse Event 
Form. Report ALL toxicities, ≥ Grade 3 for days 31-90 following last dose of protocol treatment on the S1605 Late Effects Form. Amend original 
Late Effects form to add any additional toxicities ≥ Grade 3 experienced throughout remaining follow-up period. 
Ѱ  For all patients with CIS at study entry, one urine cytology slide is required for central pathology review. See Section 12.0 for instructions. 
Ѳ  Baseline histology used to diagnose disease for eligibility (from biopsy or TURBT), per Section 5.1a. 
λ  Baseline labs (except TSH) to be obtained within a window of 3 weeks.  
 
Allowable windows 
Treatment must begin within 7 calendar days of registration. 
Allowable windows for scheduled disease assessments performed every 12 weeks is +/- 14 days, every 24 weeks is +/- 14 days. The window is to 
be calculated from the scheduled date of the procedure/assessment. 


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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Complete Response 
 
Complete Response:  Negative biopsy for high grade disease at Week 25 (± 7 days) for 
the subset of patients with a CIS component at study entry, according to local pathology 
call. In addition, patients with a CIS component who undergo negative biopsy at Week 13 
for suspicious cystoscopy and or positive cytology and have cystoscopy not suspicious for 
cancer and cytology not positive for malignant cells at Week 25 do not require repeat biopsy 
at Week 25 and will be considered to have a complete response at Week 13 and will also 
be counted as having a complete response at Week 25.   
 
10.2 
Complete Response duration  
 
Complete Response Duration:  Defined as the time from date of biopsy documenting the 
complete response to the time of first high-grade recurrence. 
 
10.3 
Progression 
 
Progression: Biopsy proven muscle invasive bladder cancer Stage ≥ T2, nodal or distant 
metastasis. 
 
10.4 
Event 
 
Event: Histologically proven first appearance of high-grade bladder cancer at Week 13 or 
later if stage ≥ T1, or Week 25 or later if stage Ta or CIS, muscle-invasive bladder cancer, 
clinical evidence of metastatic disease, high grade upper tract urothelial carcinoma, high 
grade urothelial carcinoma of the prostatic urethra, or death due to any cause. 
 
10.5 
Recurrence 
 
Recurrence: Histologically proven first appearance of high-grade bladder cancer at Week 
13 or later if stage ≥ T1, or Week 25 or later if any stage high-grade, according to local 
pathology call. 
 
10.6 
Progression-Free Survival 
 
Progression-Free Survival:  From time of registration to time of first documentation of 
progression (as defined in Section 10.3) or death due to any cause. Patients last known to 
be alive and not to have progressed are censored at the date of last contact. 
 
10.7 
Event-Free Survival 
 
Event-Free Survival: From date of registration to first documentation of event (see Section 
10.4). Patients last known to be alive and not to have recurred are censored at the date of 
last contact. 
 
10.8 
Recurrence-Free Survival 
 
Recurrence-Free Survival:  From date of registration to the first documentation of 
recurrence (as defined in Section 10.5).  Patients last known to be alive and not to have 
recurred are censored at the date of last contact. 
 
 


S1605 
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10.9 
Cancer-Specific Survival 
 
Cancer-Specific Survival:  From date of registration to date of death due to bladder cancer.  
Patients without bladder cancer death are censored at last contact date or date of non-
bladder cancer death. 
 
10.10 
Overall Survival 
 
Overall Survival:  From date of registration to date of death due to any cause.  Patients last 
known to be alive are censored at the date of last contact. 
 
10.11 
Performance Status   
 
Performance Status: Patients will be graded according to the Zubrod Performance Status 
Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Patient Populations 
 
Eligible patients are defined as registered patients who met all the pre-registration eligibility 
criteria listed in Section 5 that were in effect at the time of the 12/14/18 amendment.     The 
determination of eligibility regarding Disease Related Criteria will be based on local 
pathology review. 
 
Evaluable patients are defined as registered patients who received any amount of study 
drug (atezolizumab). 
 
Efficacy analyses will be based on patients who are determined to be both eligible and 
evaluable as defined above. 
 
Safety analyses will be based on patients who are determined to be evaluable as defined 
above.  Patients who are registered in the study but who do not receive any study drug will 
not be included in safety analyses. 
 
 


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11.2 
Estimate of Sample Size: 
 
A sample size of 135 eligible patients (evaluable) will be enrolled over 36 months with 18 
months of additional follow-up. Our goal is to enroll 70 patients with a CIS component and 
65 patients with Ta or T1 disease only. One stratum may be closed prior to accrual 
completion to ensure adequate patient numbers in both disease groups. An additional 50% 
will be enrolled to account for ineligibility or initial treatment refusal resulting in a total 
sample size of 202.  With Revision #5 (Version Date 12/14/18) a pre-registration Study 
Chair approval form was enacted which has significantly reduced the rate of ineligible 
registrations. 
 
11.3 
Analysis: 
 
There will be two co-primary aims for this study:  The first objective to be tested involves 
the complete response rate in the subset of patients with CIS (see Section 10.1).  The 
second co-primary objective involves event-free survival at 18 months for all evaluable 
patients.  A hierarchical approach will be used to test the two co-primary aims.  The CIS 
aim will be tested first.  Only if the result is statistically significant will the second primary 
objective be evaluated.  Only patients who received at least one dose of atezolizumab per 
protocol will be evaluable for these two primary objectives.  Both co-primary tests will be 
conducted at the one-sided 0.05 significance level. 
 
The first primary objective is the estimation of the CR rate in the subset of patients with 
CIS. Enrollment of 70 eligible and evaluable patients with a CIS component will be ensured.  
If the total number of patients out of 70 who respond is 28 (40%) or greater, the agent 
would be considered promising. This design has a significance level (probability of falsely 
declaring that an agent with a 30% complete response probability is worthy of further 
investigation) of 4.6%, and a power (probability of correctly declaring than an agent with a 
complete response rate of 50% is worthy of further investigation) of 96%. Seventy 
evaluable patients are sufficient to estimate the CR rate at 25 weeks (± 1 week) to within 
± 12% (95% confidence interval). Those CIS patients without a biopsy at 25 weeks will be 
assumed to be non-responders. Duration of CR is defined as the time from date of biopsy 
documenting the complete response to the time of first high-grade recurrence,and is a key 
additional secondary endpoint. With a CR rate of 50%, we would expect 35 patients would 
have a CR. We can estimate the proportion still in CR at 18 months to within ±17% (95% 
confidence interval). 
 
One interim futility assessment will be made in the CIS subset.  We will evaluate the first 
25 eligible and evaluable CIS patients for pathologic response at 25 weeks.  Since accrual 
is expected to be slow, accrual will continue while the interim evaluation is underway.   A 
favorable evaluation would be if 7 or more CRs are seen in the first 25 eligible and 
evaluable CIS patients.  This is equivalent to testing the alternative hypothesis of a 50% 
complete response rate at the one-sided alpha=0.02. If results are favorable, accrual will 
continue to a total of 70 eligible and evaluable CIS patients. 
 
The second primary endpoint is event-free survival (EFS) (as defined in Section 10.0) at 
18 months in the mixed population of patients with either CIS or Ta or T1 disease.  This 
objective will only be tested if the null hypothesis in the first co-primary objective is rejected 
as specified above.  The 18-month EFS estimate will be obtained using the method of 
Kaplan and Meier, and the Greenwood formula will be used to estimate the variance. A 
90% confidence interval will be estimated for the 18-month EFS estimate. If the lower 90% 
confidence bound excludes 20%, the investigators will conclude the regimen significantly 
improves EFS relative to historical trial data.  
 
Based on published rates (see table below), it is assumed that if the true 18-month EFS 
rate in this mixed patient population is ≤ 20%, then this regimen will not warrant further 
investigation in this setting, whereas a 30% or greater EFS rate at 18 months would be of 


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considerable interest. This study has a type I error rate (one-sided) of 0.05 and statistical 
power of 0.93. 
 
There will be one interim analysis conducted at the end of accrual. The 99% confidence 
interval around the 18 month EFS Kaplan-Meier estimate will be constructed. If the upper 
confidence bound rules out 30% then consideration will be given to reporting the results 
early due to futility. There is no adjustment to the alpha for this interim test because it is 
based on futility. We will not consider reporting early due to efficacy. Because one of the 
primary endpoints occurs at 18 months and accrual is expected to be steady but modest, 
an interim analysis of EFS prior to this point in the trial will not be informative. 
 
There are several trials with outcomes that can be used as historical controls for this trial. 
Most of these are described in Section 2.0. 
 
Drug  
Study  
Patients  
Outcome  
Valrubicin  
Steinberg 2000  
BCG-unresponsive CIS  
21% @ 3 mo  
17% @ 12 mo  
8% @ 24 mo  
Valrubicin  
Dinney 2013  
BCG-unresponsive CIS  
10% @ 12 mo  
3% @ 24 mo  
Gemcitabine  
Skinner 2013  
mostly BCG unresponsive 
CIS/Ta/T1 (89% high 
grade)  
 
28% @ 12 mo  
20% @ 24 mo  
Gemcitabine  
DiLorenzo 2010  
mix of BCG 
failure/unresponsive  
19% @ 24 mo  
Docetaxel  
Lamont 2005  
mix of BCG 
failure/unresponsive  
40% @ 12 mo  
25% @ 36 mo  
MCNA  
Morales 2015  
mix of BCG 
failure/unresponsive  
20.9% @ 12 mo 
(FDA analysis)  
rAdIFN  
Dinney 2015  
BCG unresponsive 
CIS/Ta/T1  
35% @ 1 mo  
 
Only Valrubicin is FDA approved in this setting, and is therefore the most representative 
historic control. Compared to all of these studies, our intended endpoint of 30% EFS at 18 
months would demonstrate a clear improvement in outcome.  
 
A secondary aim of interest is the assessment of EFS in the Ta/T1 subset. With n=65 
eligible and evaluable patients, there will be 71% power to detect Ho: 20% vs. Ha: 30%, 
using a one-sided alpha=0.05. Other secondary estimates and confidence intervals of 
endpoints of progression-free survival (PFS), cystectomy-free survival, bladder cancer 
specific survival (CSS) and overall survival (OS) will also be provided using Kaplan-Meier 
estimation. Short-term estimates at 18 months and long-term estimates at 5 years for these 
secondary endpoints will be of interest. Qualitative and quantitative toxicity assessment will 
be provided using CTCAE reporting. CR and adverse event rates can be estimated to 
within ± 9% (95% confidence interval). A toxicity with a true incidence of 1% (5%) has a 
69% (99%) chance of being observed at least once in this single arm trial. 
 
11.4 
Estimate of Accrual Rate 
 
Target accrual will be 4 patients per month with planned completion of the accrual in 36 
months. 
 
11.5 
Statistical Plan for Translational Aims 
 
For all analyses in this study, the investigators will consider the use of non-parametric or 
robust alternatives in the case when distributional assumptions or asymptotic 
approximations fail.  Further, for simplicity, complete follow-up will be assumed on all 


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patients, but alternative statistical approaches accommodating censoring and potential 
confounders (e.g. technical batch) will be used if necessary.  It will also be assumed that 
85% of eligible patients (60 eligible CIS patients and 115 eligible patients in total) will have 
usable samples for the specified assessment. 
 
Immunohistochemistry (Objective 1.3.b):  To assess the association between PD-L1, as 
quantified via IHC, a dichotomous indicator of positive PD-L1 expression will be created 
for each patient sample: if ≥ 5% of cells express PD-L1, then the sample will be scored as 
positive; otherwise, the sample will be negative.  Logistic regression will then be used to 
regress the dichotomous CR status of each CIS patient on the indicator of PD-L1 
expression.  Fisher’s exact test may be used if the proportion of complete responders or 
proportion of patients expressing PD-L1 is small.  Similarly, using all patients, logistic 
regression will also be used to regress dichotomous 18-month EFS status of each patient 
on the indicator PD-L1 expression.  The analysis will be repeated with CD8 expression as 
well as other markers. The type I error rate will be controlled at the two-sided alpha=0.05.  
 
For the CR endpoint in CIS patients, assuming baseline CR rate of 30%, then with a sample 
size of 70, 80% power is anticipated to detect a log odds-ratio of 1.75, 1.59, and 1.52, if 
the particular marker is positive in 25%, 35%, or 45% of the CIS patients, respectively. For 
the 18-month EFS endpoint, assuming a baseline 18-month EFS rate of 20%, then with a 
sample size of 115 patients, investigators anticipate 80% power to detect a log odds-ratio 
of 1.28, 1.19, and 1.15 if a particular marker is positive in 25%, 35% or 45% of the patients, 
respectively. 
 
RNA sequencing (Objective 1.3.b): Following preprocessing and normalization of the 
RNAseq data, it will be determined whether each patient expresses the pre-defined 
signature.  Then to determine whether pre-defined signatures are predictive of complete 
response in CIS patients, logistic regression will be used to regress CR status for each CIS 
patient on an indicator for whether each patient expresses the signature. Similarly, to 
determine whether pre-defined signatures are predictive of 18-month EFS in all patients, 
logistic regression will be used to regress 18-month EFS status for each patient on an 
indicator for whether each patient expresses the signature. This analysis will be repeated 
for each signature considered. Investigators will again consider using Fisher’s exact test if 
the CR or 18-month EFS rates or the proportion of patients expressing the signature are 
low.  Type I error rate will be controlled at the 2-sided alpha=0.05 level.  
 
For the CR endpoint in CIS patients, assuming baseline CR rate of 30%, then with a sample 
size of 70, 80% power is anticipated to detect a log odds-ratio of 1.75, 1.59, and 1.52, if 
the percentage of CIS patients expressing the signature is 25%, 35%, or 45%, respectively. 
For the 18-month EFS endpoint in all patients, assuming a baseline 18-month EFS rate of 
20% for patients not expressing the signature, then with 115 patients, investigators 
anticipate 80% power to detect a log odds-ratio of 1.28, 1.19, and 1.15 if the percentage of 
patients expressing the signature is 25%, 35% or 45%, respectively. 
 
11.6 
Data and Safety Monitoring Committee 
 
Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center and will meet at 
the Group's bi-annual meetings as necessary.  The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study. 
 
Toxicity and accrual monitoring are done routinely by the Study Chair, study statistician, 
and the Disease Committee Chair.  Monthly summary reports on adverse events, SAEs 
and treatment delays and dose modifications are reviewed by the study chair and study 
statistician.  Accrual reports are generated weekly and formal toxicity reports for a wider 


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audience are created every 6 months.  In addition, SWOG Statistics and Data Management 
Center, Adverse Event Coordinator at the Operations Office, SAE Physician Reviewer, and 
Study Chair monitor toxicity on an ongoing basis. 
 
 
12.0 
DISCIPLINE REVIEW 
 
12.1 
Central Pathology Review 
 
a. 
All patients registered on this study will undergo central pathology review to 
confirm diagnosis and determine eligibility.  Pathology material must be available 
for this purpose (see Section 5.0).  The review will verify the histologic diagnosis 
of non-muscle invasive urothelial carcinoma of the bladder and determine the 
grade and pathologic stage of the tumor.  Pathologic review will be conducted on 
an ongoing basis, but will not be verified prior to patient registration and initiation 
of study treatment. Similarly, all patients with CIS will undergo central review of 
urine cytology at 13 and 25 weeks in order to verify complete response.  All bladder 
biopsies taken to evaluate a suspicious lesion in any patient or at the mandatory 
25 week time point in patients with CIS will be reviewed centrally, but decisions to 
continue study treatment will be based on the local pathologist’s interpretation. 
 
b. 
All pathology submissions must be entered and tracked using the SWOG online 
Specimen Tracking system.  See Section 15.1b for information about this system. 
 
c. 
Pathology materials are to be submitted to the SWOG Biospecimen Bank (Lab 
#201).  The Bank will scan the slides and send to the study pathologist, M. Scott 
Lucia, M.D. 
 
All specimens must be shipped at room temperature for overnight delivery, 
Monday through Thursday (no weekend or holiday deliveries accepted). 
 
d. 
The following materials are to be submitted for review: 
 
Tissue 
 
1. 
Three (3) representative diagnostic tumor H & E stained slides. 
 
2. 
One copy of corresponding surgical pathology report. 
 
Urine Cytology (only patients with CIS component at study entry) 
 
1. 
1 urine cytology slide (This should be the routine slide used by the site to 
do the cytology.) 
 
2. 
Cytology report 
 
The tissue and cytology specimens used by the study site for diagnosis must be 
submitted.  No special specimen preparation is required. A copy of the Shipment 
Packing List produced by the Specimen Tracking system must be printed and 
placed in the pocket of the specimen bag if it has one, or in a separate resealable 
bag. 
 
 


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e. 
Specimens and corresponding reports must be submitted at the following time 
points: 
 
Tissue 
 
1. 
Baseline collection, submitted within 7 days after registration.  All tissue 
obtained within 60 days prior to registration for histologic confirmation of 
recurrent disease (see Section 5.1).  For T1 patients, tissue from the 
prestudy re-resection and original TURBT (even if > 60 days prior to 
registration) must be submitted. 
 
2. 
All subsequent biopsies for suspected recurrence including negative 
biopsies and those that show any recurrence (high or low grade). 
 
3. 
FOR PATIENTS WITH CIS DISEASE AT STUDY ENTRY:  Within 28 days 
after Week 25 biopsy. 
 
Urine Cytology 
 
1. 
FOR PATIENTS WITH CIS DISEASE AT STUDY ENTRY: Within 28 days 
after Week 13 and Week 25 disease assessments. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
NOTE: Prior to registering the first patient, someone at each site must complete the S1605 
training by reviewing the PowerPoint presentation located at: https://swog.org/required-
S1605-training and submitting a verification of completion to CTSU by filling in the required 
fields and clicking “submit”. 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than five working days 
prior to planned start of treatment). 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored clinical trials to 
register and to renew their registration annually.  To register, all individuals must 
obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to 
OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements 
per registration type are outlined in the table below. 
 
 


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Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) 
tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, 
please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
b. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including 
but not limited to: the following: 
 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the 
following criteria: 
 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 
1572 
• 
An active status on a participating roster at the registering site. 
 
 


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Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval documentation 
to the CTSU Regulatory Office. For sites using the CIRB, IRB approval 
information is received from the CIRB and applied to the RSS in an 
automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRB Manager to 
indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform 
the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
2. 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the S1605 protocol page 
located on the CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the 
protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the SWOG link to expand, then select trial protocol S1605 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided.   
 
3. 
Requirements For S1605 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted)  
• 
For applicable NCTN studies with a radiation and/or imaging (RTI) 
component, the enrolling site must be aligned to a RTI provider.  
To manage provider associations, access the Provider 
Association tab on the CTSU website at  
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers.  Sites must be linked to at least one 
IROC credentialed provider to participate on trials with an RT 
component. Enrolling sites are responsible for ensuring that the 
appropriate agreements are in place with their RTI provider, and 
that appropriate IRB approvals are in place. 
• 
Verification that at least one site staff member has reviewed the 
PowerPoint presentation as outlined in Section 13.0. 
 
4. 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval and 
Model Informed Consent to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal:  
www.ctsu.org (members’ area)     Regulatory 
Tab 
Regulatory 
Submission  
 
 


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When applicable original documents should be mailed to:  
CTSU Regulatory Office  
1818 Market Street, Suite 3000 
Philadelphia, PA 19103  
 
Institutions with patients waiting that are unable to use the Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order 
to receive further instruction and support. 
 
Delegation of Task Log (DTL):  
Each site must complete a protocol-specific DTL. The Clinical Investigator 
(CI) is required to review and electronically sign the DTL prior to the site 
receiving an Approved site registration status and enrolling patients to the 
study. The DTL application is located on the CTSU members’ website at 
www.ctsu.org. Any individual at the enrolling site on a participating roster 
may initiate the site DTL. Instructions on completing the DTL are 
embedded in the DTL. 
 
5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members section of the 
CTSU website. 
 
• 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements outlined 
by the Lead Network. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < 
https://ctepcore.nci.nih.gov/iam >) and a ‘Registrar’ role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type.  If a DTL 
is required for the study, the registrar(s) must also be assigned the OPEN Registrar task 
on the DTL.  
 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database.  OPEN can be accessed at https://open.ctsu.org or from the 
OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  To assign 
an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 
1572 in RCR the IRB number used on the site’s IRB approval.  If a DTL is required for the 
study, the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 


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OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
 
 


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13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org,  or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes 
and the affirmation of eligibility on the Registration Worksheet has been 
signed 
by 
the 
registering 
investigator 
or 
another 
investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org.  
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.   
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see below for details. 
 
 


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14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site 
Investigator) on either the LPO or participating organization roster at the enrolling 
site. To hold the RAVE CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type. To hold the Rave site Investigator role, the 
individual must be registered as an NPIVR or IVR. Associates can hold read-only 
roles in Rave. Individuals requiring write access to Rave must also be assigned 
the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on Workbenches, 
then CRA Workbench to access the home page for the CRA Workbench and follow 
the link to Rave® provided in the left-hand navigation panel.  
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page). 
 
 


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For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org.  
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS OF REGISTRATION: 
 
Submit the following: 
 
S1605 Onstudy Form 
 
S1605 Eligibility Criteria Form  
• 
Fill out electronic version in Rave 
• 
Keep paper version in patient’s records at site with registering 
investigator’s signature and date signed 
 
S1605 Pre-Registration Study Chair Approval Form 
• 
PRIOR TO PATIENT REGISTRATION. Please email completed form with 
any supporting pathology reports to S1605question@swog.org at least 
5 days prior to planned registration date  
• 
AFTER REGISTERING the patient, please add the SWOG patient ID to 
the top right corner of this form 
Upload this completed/signed form as a baseline source document in Rave 
 
Baseline Abnormalities Form 
 
Operative and Pathology Reports (If there is a re-TURBT at baseline, submit both 
reports from first and second procedure.) 
 
Cytology Report 
 
Baseline Electrocardiogram (ECG) Report 
 
Specimens as outlined in Sections 12.0. 
 
Radiology reports from all scans performed to assess disease. 
 
b. 
WITHIN 28 DAYS AFTER REGISTRATION: 
 
Submit specimens as outlined in Section 15.0 (if patient has consented). 
 
c. 
WITHIN 28 DAYS OF DAY 1 OF CYCLES 1, 2, 3, 5, 9, AND 17: 
 
Submit specimens as outlined in Section 15.0 (if patient has consented). 
 
d. 
WITHIN 7 DAYS AFTER EACH CYCLE OF TREATMENT: 
 
Submit the following: 
 
S1605 Treatment Form 
 
S1605 Adverse Event Form 
 
 


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e. 
WITHIN 28 DAYS AFTER EACH DISEASE ASSESSMENT UNTIL HIGH-GRADE 
RECURRENCE, OR MUSCLE INVASIVE DISEASE UP TO 5 YEARS 
(REGARDLESS OF TREATMENT STATUS): 
 
S1605 Disease Assessment Form 
 
Cytology Report 
 
Pathology Report (if biopsy was performed) 
 
S1605 Follow-Up Form (if patient is off protocol treatment) 
 
f. 
FOR PATIENTS WITH CIS DISEASE, WITHIN 28 DAYS AFTER WEEK 13 AND 
WEEK 25 DISEASE ASSESSMENT: 
 
Submit specimens and cytology report as outlined in Sections 12.0. 
 
g. 
BIOPSY FOR SUSPECTED RECURRENCE AT ANY TIME POINT (all patients): 
 
Submit specimens as outlined in Sections 12.0 (Required). 
 
Submit specimens as outlined in Section 15.0 (if patient has consented). 
 
Pathology report 
 
h. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice 
 
S1605 Treatment Form (final) 
 
S1605 Adverse Event Form (final; including ALL toxicities, ALL Grades for first 30 
days following last dose of atezolizumab, regardless if patient has started new 
cancer therapy) 
 
i. 
30 DAYS AND 90 DAYS FOLLOWING DISCONTINUATION OF TREATMENT: 
 
S1605 Late Effects Form (all toxicities, Grades ≥ 3 for Days 31-90 following last 
dose of atezolizumab, regardless if patient has started a new cancer therapy; 
amend original Late Effects form to add any additional toxicities ≥ Grade 3 
experienced throughout remaining follow-up period). 
 
j. 
FOR PATIENTS WHO HAVE NOT HAD HIGH GRADE RECURRENCE AT 18 
MONTHS/WEEK 73 (AT TIME OF CYSTOSCOPIC EVALUATION AND CT/MRI): 
 
Submit specimens as outlined in Section 15.0 (if patient has consented). 
 
Submit images as outlined in Section 15.2 (Required). 
 
Radiology report from the submitted 18 month scan should be uploaded as a 
source document in Rave. 
 
 


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k. 
WITHIN 14 DAYS OF HIGH GRADE RECURRENCE: 
 
If on protocol treatment: 
 
Off Treatment Notice  
 
S1605 Treatment Form (final) 
 
S1605 Adverse Event Form (final) 
 
S1605 Disease Assessment Form (final) 
 
Pathology Report 
 
Submit specimens as outlined in Section 15.0 (if patient has consented). 
 
Submit images as outlined in Section 15.2 (Required). 
 
Submit documentation supporting findings of metastatic bladder cancer, muscle-
invasive bladder cancer (e.g. pathology report) 
 
If completed/off protocol treatment: 
 
S1605 Disease Assessment Form (final) 
 
Pathology Report 
 
S1605 Follow-Up Form  
 
Submit specimens as outlined in Section 15.0 (if patient has consented). 
 
l. 
IF CYSTECTOMY IS PERFORMED (bladder removal surgery) 
 
Submit Pathology and Operative Reports from cystectomy procedure (uploaded 
as source documents in Rave) 
m. 
AFTER HG RECURRENCE, EVERY 6 MONTHS FOR YEARS 1-2, THEN 
ANNUALLY FOR YEARS 3-5: 
 
S1605 Follow-Up Form  
 
S1605 Late Effects Form (all toxicities, Grades ≥ 3 for Days 31-90 following last 
dose of atezolizumab, regardless if patient has started a new cancer therapy; 
amend original Late Effects form to add any additional toxicities ≥ Grade 3 
experienced throughout remaining follow-up period) 
 
n. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and S1605 End of Study Form and a final S1605 
Treatment Summary Form and S1605 Adverse Event Summary Form (if the 
patient was still on protocol treatment) or S1605 Follow-Up Form (if the patient was 
off protocol treatment) documenting death information. 
 
o. 
WITHIN 4 WEEKS OF CONSENT WITHDRAWAL, LOST TO FOLLOW-UP OR 
MAXIMUM FOLLOW-UP OF 5 YEARS: 
 
S1605 End of Study Form 
 
 


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p. 
PRIOR TO JUNE 1, 2020 (ALL REGISTERED PATIENTS WHO RECEIVED ANY 
PROTOCOL TREATMENT) 
 
If OFF protocol treatment: 
 
Submit S1605 Concomitant Medications Form 
(all concomitant medications received while on protocol treatment must be 
reported)  
 
If ON protocol treatment: 
 
Submit S1605 Concomitant Medications Form AND form must be up to date with 
current concomitant medication data as of June 1, 2020 
 
q. 
WITHIN 30 DAYS AFTER THE DISTRIBUTION OF REVISION #9 (protocol 
version date 09/20/2021) 
 
Submit the following: 
 
Baseline TSH & T4 results on the S1605 Onstudy Form (amend original Onstudy 
form in Rave) 
 
S1605 Lab Values Form for each cycle of protocol treatment patient received 
(if labs were repeated within a treatment cycle, all repeated labs must be reported 
as well) 
 
Any additional labs or clinical workup done to assess or monitor an adverse event 
while on protocol treatment (e.g. cultures, EKG, additional labs not listed on the 
S1605 Lab Values Form) – describe in the Comments section of the S1605 
Adverse Event Form containing the associated toxicity 
 
r. 
WITHIN 15 DAYS AFTER SUBMISSION OF ALL DATA REQUESTED IN 
REVISION #9, RESOLUTION OF ALL QUERIES, AND CONFIRMATION IS 
RECEIVED FROM THE SWOG STATISTICS AND DATA MANAGEMENT 
CENTER THAT THE PATIENT’S CHART IS LOCKED IN RAVE 
 
Electronic Signature Page 
(Investigator must check the box and e-sign this page in Rave attesting to the 
completeness and accuracy of the data, see section 18.5 for more information) 
 
 
 
 


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15.0 
SPECIAL INSTRUCTIONS 
 
See Section 12.0 for mandatory central pathology eligibility review submission information. 
 
15.1 
Translational Medicine and Banking 
 
Specimens for translational medicine and banking are optional for the patient.  The SWOG 
Specimens Submission webpage for the SWOG Biospecimen Bank – Solid Tissue, (Lab 
#201), is located at the following URL:   
https://www.swog.org/member-resources/biospecimen-resources/solid-tissue-specimen-
submission.   
 
a. 
If the patient consents, specimens must be submitted as follows (see Section 9.0): 
 
1. 
FFPE Tissue from TURBT for IHC, RNA-seq, and Banking 
 
 
a. 
FFPE Tissue Specimen Submission Time Points: 
 
i. 
Baseline −SUBMITTED WITHIN 28 DAYS AFTER 
REGISTRATION (PRESTUDY TURBT) 
 
 
Positively Charged Unstained Slides: 
 
Number of Slides 
Thickness  Type of Testing 
Five (5) 
5 mcM  
IHC 
 
Sections of Scrolls*: 
 
Number of Scrolls 
Thickness 
Type of Testing 
Four (4) 
5 mcM 
RNA-seq 
Eleven (11) 
10 mcM 
Banking for future 
studies ** 
* NOTE:  another term for this type of tissue preparation 
is “curls”. 
** May substitute FFPE block for unstained slides and 
scrolls. However, 3 H&E stained slides are still required 
per Section 12.0. 
 
If adequate tissue specimen is not available from 
TURBT to submit for all of the slides and scrolls listed 
at any time point above, specimens for RNA-seq will 
be prioritized over IHC, and these over banking. 
 
ii. 
AT ANY TIME BIOPSY IS PERFORMED FOR SUSPECTED 
RECURRENCE AND AT REQUIRED WEEK 25 BIOPSY: 
 
Positively Charged Unstained Slides: 
 
Number of Slides 
Thickness  Type of Testing 
Five (5) 
5 mcM  
IHC 
 
 
 


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Sections of Scrolls: 
 
Number of 
Scrolls 
Thickness  Type of Testing 
Four (4) 
5 mcM 
RNA-seq 
Six (6)   
5 mcM 
Banking for future 
studies ** 
** May substitute FFPE block for unstained slides and 
scrolls. However, 3 H&E stained slides are still 
required per Section 12.0. 
 
b. 
FFPE Tissue Specimen Collection and Submission Instructions 
 
SLIDES:  For IHC, sites will submit specimens of tumor-containing 
FFPE tissue as sections on positively charged unstained slides. 
 
SCROLLS:  For RNA-seq and banking, sites will section tumor-
containing FFPE blocks on site and submit as scrolls in Eppendorf 
tubes.  For banking submission only, sites may submit tumor-
containing FFPE blocks instead of scrolls. 
 
Tissue should be sectioned as close to date of shipment as 
possible (not more than 2 weeks prior to shipment).  Sections 
and scrolls should be stored at 4ºC; batch shipment is allowed. 
 
Tissue blocks can also be submitted, in which case the sites are 
requested to estimate that enough tissue is submitted to meet the 
above listed section requirements. 
 
Follow packaging instructions on the SWOG Specimen 
Submission webpage.  Ship to the SWOG Biospecimen Bank – 
Solid Tissue, (Lab #201). 
 
2. 
Whole Blood for Banking 
 
a. 
COLLECTED PRIOR TO TREATMENT START, SUBMIT 
WITHIN 28 DAYS AFTER REGISTRATION 
 
Collect 5 mL whole blood in one 5 mL sodium-citrate tube.  Note 
that no additional whole blood processing is required prior to 
freezing.  Freeze whole blood in sodium-citrate at -80°C until 
shipment.  Whole blood may be batch-shipped on dry ice as long 
as all specimens are shipped within 3 months of collection. 
 
If this collection is missed prior to treatment start, please collect at 
next visit. 
 
Follow packaging and shipment instructions on the SWOG 
Specimen Submission webpage. Ship to the SWOG Biospecimen 
Bank – Solid Tissue (Lab #201). 
 
b. 
DAY 1 OF CYCLES 1, 2, 3, AND 5 
 
Prior to atezolizumab administration on these days, collect 
peripheral blood in lithium heparin-coated vacutainer blood 
collection tubes. Use the processing worksheet included in the kit 
provided by the SWOG Biospecimen Bank; required data fields 
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specimens.  Immediately transfer 2 mL of the blood to the 15 mL 
conical tube provided in the kit. Immediately add the Proteomic 
Stabilizer (PROT1) to the conical tube and mix gently. Incubate 
for 10 minutes at room temperature and then evenly distribute into 
labeled, 2 mL cryovials. Store the cryovials at -80°C until 
shipment. Blood may be batch-shipped on dry ice. Ship within 3 
months after collection. 
 
Please refer to instruction sheet included with the specimen 
kit (Instructions for S1605) for complete Blood Collection and 
Processing Information. 
 
3. 
Urine for banking 
 
a. 
Urine Specimen Submission Time Points 
 
i. 
DAY 1 OF CYCLES 1, 5, 9, AND 17 
 
ii. 
AT WEEK 73 
 
b. 
Urine Specimen Collection and Submission Instructions 
 
Prior to or after atezolizumab administration, collect approximately 
30 mL of urine mid-stream in a sterile urine cup. 
 
Aliquot collected urine into 15 mL conical tubes, centrifuge 10 
minutes at 1,000g (4ºC), and then freeze (-80ºC) upright until 
shipment.  Urine may be batch-shipped.  Ship to the SWOG 
Biospecimen Bank – Solid Tissue (Lab #201). 
 
b. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the online 
system via the CRA Workbench. To access the CRA Workbench, go to the SWOG 
Web site (http://swog.org) and logon to the Members Area. After you have logged 
on using your SWOG roster ID number and password, click on the CRA 
Workbench link to access the home page for CRA Workbench website. Non- 
SWOG users may log into SpecTrack using their CTSU UserID and password on 
the SpecTrack login page located at  
https://crawb.crab.org/SpecTrack/Logon.aspx (select the option “SWOG – SWOG 
– CTSU”).  SpecTrack start-up instructions (both written and demo) are available 
after signing in to SpecTrack. 
 
A copy of the Shipment Packing List produced by the online Specimen Tracking 
system should be printed and placed in the pocket of the specimen bag if it has 
one, or in a separate resealable bag. The Specimen Submission Form is NOT 
required when the online system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org. For 
procedural help with logging and shipping specimens, there is an introduction to 
the system on the Specimen Tracking main page 


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(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); 
or 
contact 
the 
SWOG Statistics and Data Management Center at 206/652-2267 to be routed to 
the Data Coordinator for further assistance. 
 
c. 
Specimen Collection Kits 
 
S1605 laboratory kits containing the Smart reagent (PROT1) are now 
available for ordering. The whole blood specimens noted in Section 
15.1a.2b. (whole blood collected on Day 1 of Cycles 1, 2, 3 and 5) must 
be submitted and processed per the instructions provided in the kit. 
 
Note: The Cycle 1 specimen is required for submission of downstream 
specimens. If a Cycle 1 blood specimen processed with the provided 
PROT1 buffer has not been submitted, then sites should not submit follow-
up whole blood PROT1 specimens. 
 
It is preferred that kits are ordered for registered patients only, because 
these are uncommon reagents being used for this study and waste should 
be prevented. If sites can order before noon Eastern, then they should 
receive the kits 3 – 4 business days after the request, if not sooner.  
 
The kits should be ordered in enough time to receive them prior to baseline 
collection and can be ordered online at:  
https://ricapps.nationwidechildrens.org/KitManagement. 
 
d. 
TruCulture – All Sites are Eligible to Participate 
 
When you are preparing a patient for registration, please order a TruCulture kit  
online at https://ricapps.nationwidechildrens.org/KitManagement. Kits will not be 
provided to sites before an eligible patient is identified. 
 
Upon receipt of the kit, read the instructions included.  Maintain the TruCulture 
syringes at -20 C until time of use. 
 
Prior to atezolizumab administration on Cycle 1 Day 1 and again on Cycle 2 Day 
1, collect and process blood as described in the instructions provided in the kit. 
 
15.2 
Submission of Images for Banking (Required) 
 
All participants will undergo CT or MRI imaging of the abdomen and pelvis at Week 73 
after registration if they have not had a high-grade recurrence.  Images must be locally 
read and interpreted by the local site radiology services.  Imaging exams must then be 
submitted electronically via the AG Mednet service as described below.  Specific 
information about the imaging workflow and instructions can be found at on the S1605 
Desktop Agent application. 
 
a. 
Electronic Submission Set-Up 
 
To request access, email the S1605 trial administration at: 
agmednetadmin@swog.org and provide the following information: 
• Contact Name 
• Email Address 
• Phone Number 
• Site Name 
• NCI Site Code 
• Address 
• Trial Name 
• Trial ID 
• Date 


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b. 
Registration via the AG Mednet Portal 
 
1. 
If your site is qualified to participate in the trial, the SWOG Trial 
Administrator will invite you to the trial via the AG Mednet Portal. When 
you are added, you will receive a welcome email notification prompting 
you to register in the portal:  https://portal.agmednet.net. 
 
2. 
Complete the 2 pages of registration information. This includes creating 
your own username and password and a challenge question and answer. 
 
3. 
When you are finished with registration, the portal will display a 
“Registration Complete” page. At this point you now have access to the 
trial. After you download the Desktop Agent, you will be able to login with 
your new username and password. You will also receive a registration 
confirmation email notification. 
 
c. 
Download the Desktop Agent and Login 
 
There are a few basic requirements that must be in place in your computer in order 
to use the AG Mednet Desktop Agent: 
 
• 
Computer/Operating System: 
o 
Windows 7; Windows 8, Windows 10 
o 
Mac OS X version 10 (rosemite), 10.11 (El Capitan) and above. 
• 
Disk Space/Memory: 
o 
Sufficient disk space to store temporary local copies of image exams; 
o 
Minimum of 1 GB of memory. 
• 
Internet Access and Compatible Browser: 
o 
Internet Explorer Version 11, Mozilla Firefox Version 44, Google 
Chrome Version 48.x (Windows only), 
Apple Safari version 9.x or newer (Mac only). 
 
• 
Java 8: 
o 
You need to have Java 8 installed on your Windows or Mac computer 
to use AG Mednet. 
o 
It is likely you already have Java installed. If you do not, you will be 
prompted to download it after launching the Desktop Agent. 
o 
We do support the last minor version as well, Java 7 Update 80 
 
• 
AG Mednet Desktop Agent: 
o 
For 
your 
first 
upload, 
visit 
the 
AG 
Mednet 
Portal: 
https://portal.agmednet.net. Click on “Launch Desktop Agent.” 
o 
For subsequent uploads, you may launch the Desktop Agent from the 
AG Mednet Portal, or double-click the “AG Mednet Desktop Agent” 
icon on your computer desktop. 
 
d. 
Submission (DICOM Exam) 
 
1. 
Click on the tab “Locate Exam” (top of screen) 
 
2. 
For CD/DVD, load a disc into your machine 
 
3. 
A normal directory tree will be visible (close any DICOM viewers that may 
pop-up). Select the location of your DICOM files (i.e., the CD/DVD drive) 
or your PACS server. (NOTE: if sending from a PACS or Modality, use the 


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DICOM Query or DICOM Receive Tab. Further details are available in the 
user guide on the Welcome Tab) 
 
4. 
Find the time-point you wish to submit and select the “DICOMDIR” file and 
click “Import Exam.” Click “Close” when complete* 
 
5. 
Click the “Exam List” tab (top of screen) 
 
6. 
Select the exam you want to submit from “Available Exams” by clicking on 
a row within the table. In the image preview, you will see a picture of the 
data selected. Please check this is what you intend to submit. If not, select 
a different exam or go back to step A or E and select a different exam from 
the exam list. 
 
7. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Assign Exam to Trial.” In pop-up box, select S1605 from drop-down list 
and click “Assign Trial.” 
 
8. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Deidentification” and click “Do Task.” 
 
9. 
To complete the submission, select “Upload Exam” and then “Do Task.” 
10. In the pop-up box, click into the first blank cell under “De-identified 
Value.” Follow the on screen guidance and enter required data. Then click 
the next blank cell below the first and repeat until all blank cells are 
populated. As you complete these cells, the red cross will turn into blue 
checks. If a red cross remains after data has been entered, please check 
that the data is correct and change if applicable. 
 
10. 
In the pop-up box, click into the first blank cell under “De-identified Value.” 
Follow the on screen guidance and enter required data. Then click the next 
blank cell below the first and repeat until all blank cells are populated. As 
you complete these cells, the red cross will turn into blue checks. If a red 
cross remains after data has been entered, please check that the data is 
correct and change if applicable. 
 
 
11. 
Click out of the cells and click “De-identify” (bottom of pop-up). AG Mednet 
will then remove any personal patient information from the DICOM 
metadata fields and replace this information with the study specific data 
you entered in the table. Click close when complete. 
 
12. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Transmittal Form” and click “Do Task.” The Data Transmittal Form will 
open. Complete all mandatory fields according to the study protocol. If you 
attempt to save the form without completing all mandatory fields, an alert 
will appear, prompting you to complete the remaining fields. If you want to 
print the form, click the “Print” button prior to saving. When the form is 
complete, click the “Save” button. 
 
13. 
In “Available Tasks for Selected Exam” (bottom left of screen), click 
“Upload Exam” and click “Do Task.” 
 
14. 
Data will now be transmitted. Upload time is variable (depending on 
network connection and the size and number of images), but AG Mednet 
can be left running in the background and the computer used for other 
work. Once the data has been transmitted, a message will pop-up and AG 
Mednet can be closed. 


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15. 
You can import new exams and process them during the upload. 
 
16. 
After 15 minutes of inactivity, the Desktop Agent will lock out. However, 
this does not interfere with the upload. You only need to log back in if you 
want to import another exam. 
 
*In most cases, a DICOMDIR file will be generated by scanners. However, 
if this is not the case, please select “All Files” from the dropdown box at 
the bottom of the “DICOM Import” screen. Data can then be selected 
manually from the directory tree and “Import Exam” clicked. The process 
is then the same as where a DICOMDIR file exists. 
 
Note: The person responsible for activating the desktop agent 
should be involved in submitting the exams as the Desktop Agent 
requires specific log-in verification. All questions regarding AG 
Mednet use should be directed to 888-9AGMEDNET, and hit 2 for the 
support option. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
 


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Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines in addition to the provisions in the 
"Intellectual Property Option to Collaborator" 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agent in this study: 
 
1. 
Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of 
the NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative Agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data"): 
 
a. 
NCI will provide all Collaborators with written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations which would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 


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4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential 
and proprietary data, in addition to the Collaborator(s)'s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) 
for courtesy review as soon as possible and preferably at least three (3) days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the 
proceedings.  Press releases and other media presentations must also be forwarded to 
CTEP prior to release.  Copies of any manuscript, abstract and/or press release/media 
presentation should be sent to: 
 
E-mail:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly 
basis by FTP burst of data.  Reports are due January 31, April 30, July 31, and October 31.  
Instructions for submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html). 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. 
 
(Directions for routine reporting are provided in Section 14.0.)  Additionally, certain 
adverse events must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. The following guidelines prescribe expedited 
adverse event reporting for this protocol. 
 
 


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b. 
Reporting Method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS. 
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1. 
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection. 
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent as part of the trial.  Reporting requirements are provided in 
Table 16.1.  The investigational agent used in this study is atezolizumab. (Please 
note:  The post dosage expedited reporting requirement window has been 
extended to 90 days rather than the normal 30-day requirement.)   If there is any 
question about the reportability of an adverse event or if on-line CTEP-AERS 
cannot be used, please telephone or email the SAE Specialist at the Operations 
Office, 210/614-8808 or adr@swog.org, before preparing the report. 
 
 


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Table 16.1: 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 90 Days of the Last Administration of the Investigational 
Agent/Intervention1 Atezolizumab 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or  Section 
16.1f.   
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 90 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
May 5, 2011 
 
f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 1 and Early Phase 2 Studies Utilizing an Agent 
under a CTEP IND: 
 


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1. 
Group-specific instructions 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements In 
addition, you may be asked to submit supporting clinical data to the 
SWOG Operations Offices in order to complete the evaluation of 
the event.  If requested, the supporting data should be sent within 
5 calendar days by fax to 210-614-0006.  Supporting clinical data 
submitted should include: 
 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical source documentation of the event. 
• 
If applicable, and they have not yet been submitted to the 
SWOG Statistics and Data Management Center copies of 
Off Treatment Notice and/or Notice of Death. 
 
2. 
The following AEs are considered adverse events of special interest 
(AESI) for this protocol and require expedited reporting via CTEP-
AERS.  Unless otherwise specified in the list below, events are to be 
reported regardless of grade or attribution: 
 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: 
 
diabetes 
mellitus, 
pancreatitis, 
hyperthyroidism, hypophysitis, and adrenal insufficiency 
• 
Hepatitis 
• 
ALT 10  ULN  
• 
AST > 10 x ULN 
• 
Systemic lupus erythematosus 
• 
Neurological 
disorders: 
Guillain-Barré 
syndrome, 
myasthenic 
syndrome 
or 
myasthenia 
gravis, 
and 
meningoencephalitis 
• 
Events suggestive of hypersensitivity, cytokine release, 
influenza-like illness, systemic inflammatory response 
syndrome, systemic immune activation, or infusion related 
reactions  
• 
Nephritis  
• 
Ocular toxicities (e.g., uveitis, retinitis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis  
• 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, 
myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g. Stevens-Johnson 
Syndrome, dermatitis bullous, toxic epidermal necrolysis) 
• 
Cases of potential drug-induced liver injury that include an 
elevated ALT or AST in combination with either an 
elevated bilirubin or clinical jaundice, as defined by Hy's 
Law and based on the following observations: 
o 
Treatment-emergent ALT or AST > 3 x ULN (or > 3 x 
baseline value in disease states where LFTs may be 
elevated at baseline) in combination with total bilirubin > 
2 x ULN (of which ≥ 35% is direct bilirubin) 
o 
Treatment-emergent ALT or AST > 3 x ULN (or > 3 x 
baseline value in disease states where LFTs may be 
elevated at baseline) in combination with clinical 
jaundice 


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• 
Suspected transmission of an infectious agent by the study 
treatment, as defined below: 
• 
Any organism, virus, or infectious particle (e.g., prion 
protein 
transmitting 
transmissible 
spongiform 
encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an 
infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient 
exposed to a medicinal product.  This term applies only 
when a contamination of study treatment is suspected. 
 
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
3. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following 
treatment with an agent under an NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the 
initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf  
 
4. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf. 
 
A copy of the report and the following supporting documentation must 
also be submitted to SWOG Operations Office within 30 days by fax to 
210-614-0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL 
/MDS diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 


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San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the 
report must be submitted for the most recent trial. 
 
 
h. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss  Pregnancy loss is defined in CTCAE as “Death in 
utero.” Pregnancy loss should be reported expeditiously as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
A Pregnancy loss should NOT be reported as a Grade 5 event under 
the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEP-AERS recognizes this event as a patient death. 
 
3. 
Death Neonatal  Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth  A neonatal death should be 
reported expeditiously as Grade 4 “Death neonatal” under the General 
disorders and administration SOC.   
 
Neonatal death should NOT be reported as a Grade 5 event under the 
General disorders and administration SOC as currently CTEP-AERS 
recognizes this event as a patient death. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at:   
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 
 
 
 
 


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17.0 
BIBLIOGRAPHY 
 
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Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of non-muscle invasive 
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Lamm DL. Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North 
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Rosevear HM, Lightfoot AJ, Birusingh KK, et al. Factors affecting response to bacillus Calmette-
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Jarow JP, et al. Urology 83:262-265, 2014. 
 
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Lerner SP, et al. Bladder Cancer 1:29-30, 2015. 
 
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Jarow JP et al, Bladder Cancer 1:133-136, 2015. 
 
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Steinberg G, Bahnson R, Brosman S, et al. Efficacy and safety of valrubicin for the treatment of 
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Skinner EC, Goldman B, Sakr WA, et al. SWOG S0353: Phase II trial of intravesical gemcitabine 
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Denzinger S, Fritsche HM, Otto W et al. Early versus deferred cystectomy for initial high-risk pT1G3 
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Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on non-muscle-invasive urothelial 
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Shabsigh A, Korets R, Vora KC, et al.  Defining Early Morbidity of Radical Cystectomy for Patients 
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Aziz A, May M, Burger M, et al.  Prediction of 90-day mortality after radical cystectomy for bladder 
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Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer; 12: 
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Petrylak DP, Powles T, Bellmunt J, et al. A phase Ia study of MPDL3280A (anti-PDL1): Updated 
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Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally advanced 
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chemotherapy: a single-arm, multicentre, phase 2 trial.  Lancet 387:1909-1920, 2016. 
 
26  
Plimack ER, Bellmunt J, Gupta S, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: 
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AB Apolo. Avelumab (MSB0010718C; anti–PD-L1) in patients with metastatic urothelial carcinoma 
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4501). 
 
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Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the 
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34  
Mangsbo SM, Sandin LC, Anger K, et al. Enhanced tumor eradication by combining CTLA-4 or PD-
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Vandeveer A, Fallon J, Tighe R, et al. Systemic immunotherapy of superficial mouse bladder 
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ImmunoTher Cancer, 3 (Suppl 2):P70, 2015. 
 
36  
de Boisferon MH, Bichat F, Mignard C, et al. Efficacy of PD-1 / PD-L1 pathway disruptors in 
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Carthon BC, Wolchok JD, Yuan J, et al. Preoperative CTLA-4 blockade: tolerability and immune 
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38  
Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in 
metastatic bladder cancer. Nature; 515: 558-562, 2014. 
 
39  
Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally advanced 
and metastatic urothelial carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial.  Lancet 387:1909-1920, 2016. 
 
40  
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metastatic bladder cancer. Nature; 515: 558-562, 2014. 
 
 
 
 
 
 


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18.0 
APPENDIX 
 
18.1 
Translational Medicine Studies 
 
18.2 
Specimen Banking and Translational Medicine Material Instructions for SWOG 
Biospecimen Bank (BB) 
 
18.3 
Quality Assurance Auditing and Monitoring 
 
18.4 
S1605 Pre-Registration Study Chair Approval Form 
 
18.5 
Investigator Electronic Signature 
 
 
 


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18.1 
Translational Medicine Studies  
 
Justification 
 
Checkpoint Blockade 
 
Cancer immunotherapy via immune checkpoint blockade has become an exciting and 
rapidly evolving treatment paradigm across multiple tumor types, including bladder cancer. 
Multiple checkpoint molecules have been identified that dampen or inhibit both CD4+ and 
CD8+ T-cell activation in peripheral tissues. One of these suppressive co-signaling 
pathways is the programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) axis. 
Binding of PD-L1 and its relative PD-L2 to the PD1 receptor conveys a state of immune 
tolerance in the tumor microenvironment. Tumor infiltrating lymphocytes recruited to this 
environment fail to manifest effector function despite abundance of antigen presentation 
on antigen presenting cells including tumor cells themselves. 
 
The PD1/PD-L1 axis can be inhibited via monoclonal antibody blockade of either receptor 
or ligand. High quality clinical evidence is mounting supporting a role of PD1/PD-L1 based 
therapy. The PD-L1 antibody atezolizumab is an engineered human IgG1 that was 
approved by the FDA in 2016 as a second line therapy after cisplatin-based chemotherapy 
in metastatic urothelial carcinoma. The Phase II trial that led to this approval reported on 
310 evaluable patients, of whom 45 (15%) demonstrated an objective response, and the 
response was ongoing at the time of reporting in 38 (84%) of these patients. (1) 
 
Markers of Response To Checkpoint Inhibitors 
 
In the Phase I and II studies of patients with metastatic bladder cancer that progressed on 
cisplatin-based chemotherapy, the immunohistochemical expression of PD-L1 in the 
tumor-infiltrating immune cells (lymphocytes, macrophages, dendritic cells) but not in the 
tumor cells was predictive of response to atezolizumab. (2,3) Of the 30 patients with 2-3+ 
PD-L1 expression in the Phase I trial, 43% experienced an objective response, but only 
11% of the other 37 patients with 0-1+ PD-L1 expression responded. Of the 100 patients 
with 2-3+ PD-L1 expression in the Phase II trial, 26% experienced an objective response, 
but only 8 and 11% in the patients with 0 and 1+ PD-L1 expression, respectively. Similar 
findings have been made with other checkpoint inhibitors in metastatic bladder cancer, and 
across multiple other cancers. 
 
Similar to PD-L1 expression in tumor infiltrating immune cells, simple infiltration by CD8+ 
cytotoxic T-cells has been shown to predict response to atezolizumab in the Phase II trial. 
(4)  This has been described in other cancers as well. For example, a higher density of 
CD8+ cells at the invasive tumor margin was observed in melanoma patients responding 
to pembrolizumab compared to non-responders. (5) This implies that these CD8+ T-cells 
have been rendered ineffective by the PD-1/PD-L1 axis, but inhibition of this axis disinhibits 
the cytotoxic T-cells and they are able to exert an anti-tumor effect. Presence of CD4+ cells 
has not been shown to be predictive, although the subset of FOXP3+ T-regulatory cells 
have been implicated as markers of chemoresistance in muscle invasive bladder cancer 
and warrant further investigation. (6) CTLA4 and fractalkine (CX3CL1) are further potential 
markers that have been reported to have predictive value across different cancers treated 
with atezolizumab. PD-L2 IHC has not shown a correlation to response to PD-L1 inhibition.  
 
Gene expression signatures derived from whole transcriptome analyses offer the 
advantage of simultaneous assessment of multiple genes and signaling pathways, with 
potential for more robust prediction. These signatures incorporate tumor and stromal 
elements in one marker that does not, for example, allow separation of PD-L1 expression 
in tumor versus tumor-infiltrating immune cells. Ribas discovered and tested four different 
immune signatures (“Interferon-gamma 10-gene”, “Expanded-immune 28-gene”, “TCR-
signaling” and “Denovo” signatures) in patients with metastatic melanoma receiving 
pembrolizumab (KEYNOTE-001), and noted correlations to objective response rates and 
progression-free survival. (7) Likewise, the presence of IFNG and/or IFNA gene expression 


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signatures identified tumors that were sensitive to immune checkpoint blockade, whereas 
tumors that contained deletions involving the IFNA locus (and therefore lacked IFN gene 
signatures) were resistant.  (8) 
 
Neoantigen burden has been identified as a marker of response to immune-targeting 
agents. (9) The rationale for this is that somatic mutations can result in the exposure of 
antigenic peptides by the tumor cells to the immune system. Recognition of neoantigens 
appears to be an important component of cancer immunotherapy. One would therefore 
expect tumor types with high numbers of mutations to be characterized by strong T cell 
responses and to be particularly sensitive to immunotherapy.  Mutational load correlated 
to clinical response in non–small cell lung cancer treated with PD-1 blockade and 
melanoma treated with CTLA4 blockade. (10,11) Bladder cancer is known from The 
Cancer Genome Atlas’ (TCGA) pan-cancer analysis to have one of the highest burdens of 
somatic mutations, which should translate into high neoantigen load. In the phase 2 trial of 
atezolizumab in patients with metastatic urothelial carcinoma, mutation load correlated with 
objective response rate and efficiently stratified overall survival. (12). 
 
Building on this same concept, Le et al. reported that deficiency in DNA mismatch repair 
(MMR) is highly correlated to response to pembrolizumab in colorectal cancer (CRC) and 
11 other advanced solid tumors (bladder cancer was not included). (13) The objective 
response rate was 53% (46/86) for all MMR-deficient tumors, and an additional 23% of 
patients had stable disease. A complete response was observed in 21% of patients. In a 
previous report in fewer patients, whole-exome sequencing revealed a mean of 1782 
somatic mutations per tumor in MMR-deficient tumors, as compared with 73 in MMR-
proficient tumors, and high somatic mutation loads were associated with prolonged 
progression-free survival. (14) MMR status is determined by analysis of microsatellite 
stability. Microsatellites are regions of repetitive DNA where particularly frequent somatic 
mutations are found when mismatch repair pathways are deficient. The FDA recently 
approved the use of pembrolizumab for the 2nd line treatment of advanced MMR-deficient 
solid tumors regardless of tissue of origin. 
 
 
We hypothesize that vivo inflammatory response to a checkpoint inhibitor may predict 
response, and we propose to utilize a whole blood syringe-based device called the 
TruCulture System to test this a priori. This system permits us to measure immune 
responses induced by specific immune stimulants. Myriad Rules Based Medicine (RBM) is 
a commercial provider of TruCulture tubes. The basic system consists of a single, self-
contained syringe, which is preloaded with superantigen (SEB) for T-cell activation. After 
a fixed interval of incubation, performed at the point-of-care, culture supernatants can be 
frozen and stored for centralized testing in a CLIA certified laboratory. A broad panel of 
cytokines can be measured. Genentech has worked with RBM to develop customized 
tubes that contain atezolizumab alone or in combination with SEB. The hypothesis an 
enhanced cytokine response after co-stimulation with SEB and atezolizumab will predict 
favorable treatment response. The appeal of these assay systems for use in personalized 
immune-oncology is their ease of use, and the ability to implement them at the bedside of 
patients, thus minimizing technical error introduced by sample collection and manipulation 
(e.g., ficoll separation, freezing/thawing procedures). Here we propose to test the 
inflammatory response to atezolizumab in the TruCulture System prior to the first dose of 
atezolizumab and three weeks after the first dose, and to correlate this to subsequent 
treatment response. The results of this part of the study could lead to a functional immune 
assay that could be developed as a companion diagnostic. 
 
Recent efforts have also focused on identification of circulating immune cells for prediction 
of response to checkpoint blockade. Differences in circulating immune cells, such as an 
increased abundance of non-classical monocytes and increased absolute lymphocyte 
counts, have been associated with response to ipilimumab. (15)  Furthermore, a recent a 
study by Huang et al., investigated the changes in circulating T cell populations in two 
cohorts of patients with stage IV melanoma treated with pembrolizumab. The majority 
(74%) of patients exhibited an immunological response to therapy, identified as an increase 


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in proliferating (Ki67+) CD8+PD-1+ T cells. The abundance of these cells alone was not 
predictive of response to therapy. However, when normalized to pre-treatment tumor 
burden, their abundance during the peak immunological response (3-6 weeks following the 
start of treatment) was predictive of response to therapy and overall survival.  (16)  
Changes in circulating immune cells have also been found to reflect changes in disease 
states or progression in other cancers. For example, collaborators at the Vancouver 
Prostate Centre (A. Zoubeidi) have identified PD-L1 positive dendritic cells by flow 
cytometry in a high proportion of patients with castrate resistant prostate cancer. (17) 
 
In this trial we propose to analyze peripheral blood cells as a surrogate marker for altered 
tumor-associated immune responses to predict response to atezolizumab. We will 
compare the circulating immune cells with immune-related gene expression patterns of the 
primary tumor. While tumor immune milieu can only be directly measured at the time of 
biopsy, peripheral immune cells can be sampled longitudinally at multiple time points by a 
simple blood draw. This provides additional insight into the dynamics of the tumor immune 
response before and after therapy with atezolizumab. We will analyze the peripheral 
immune cells before therapy and at 3, 6 and 12 weeks after starting therapy. 
 
 
Urine-based genomic test for detection of bladder cancer recurrence 
 
Voided urine offers an abundant supply of cell free and cell associated DNA for genomic 
analysis. With the advent of affordable next generation sequencing, as well as enhanced 
understanding of the genomic landscape of urothelial carcinoma of the bladder, it is now 
feasible to test the genomic profile of urine DNA as a detection marker in non-muscle 
invasive bladder cancer. Allelic burden of specific mutations, copy number changes and 
translocations will be monitored to track disease burden. Analysis of cell associated and 
selected fractions of cell free DNA may also provide a measure of genomic heterogeneity 
within pre-malignant bladder epithelium and allow monitoring of potential landscaper 
mutational events and their response to therapy. The non-invasive nature of urine 
collection permits frequent serial monitoring of genomic response, tumor evolution and 
disease burden.  
 
We established an assay to identify bladder tumor associated mutations in urine using 
broad and ultra-deep next generation DNA sequencing of over 100,000 genomic loci 
(unpublished). Custom sample preservation, molecular biology, and mutation calling 
software were developed and validated on over 700 reference samples. A bladder cancer 
diagnostic classifier was then designed using independent clinical cohorts for training 
(n=34) and test (n=114) on clinical urine samples of both cancer and non-cancer patients. 
In the validation set, the assay achieved a sensitivity of 93%, specificity of 89%, and 
incidence adjusted negative predictive value (NPV) of 99.4%. The genomic assay is 
performed in a CLIA certified laboratory and the algorithm has been locked. 
 
Experimental approach, validated assays employed and expertise of PI: 
 
Immunohistochemistry 
 
IHC for PD-L1 will be performed by Genentech/Roche or in an external commercial 
laboratory designated by Genentech/Roche using a proprietary antibody (either SP-142 or 
SP-263) and validated clinical-grade methodology as used in their prior and ongoing 
clinical trials in bladder and other cancers. (18) Researchers from the Genentech/Roche 
designated external lab will score the PD-L1 staining intensity using their established 
scoring system, rating both tumor cells and immune cells as IHC 0, 1, 2, or 3 if < 1%, ≥ 1% 
but < 5%, ≥ 5% but < 10%, or ≥ 10% of cells are PD-L1 positive, respectively. 
 
IHC will also be performed with anti-CD8 antibody. Image analysis will be used to 
determine the number of CD8+ cells in specified regions of the tissue, including: i) tumor, 
ii) invasive front (the boundary between malignant and nonmalignant tissue), and iii) normal 


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tissue.  (19) CD8+ lymphocyte density will be calculated in each region using an algorithm 
described in Cuka et al. (20)  
 
Patients with CIS disease will be undergoing bladder biopsy at the 25 week time point. A 
minority will have residual/recurrent bladder tumor, but normal tissue from the site of the 
prior tumor will be available from all CIS patients for analysis. At this time point patients will 
have completed 8 cycles of atezolizumab therapy, and characteristics of the tissue may 
suggest markers of resistance and response to the drug. IHC will be performed to analyze 
the same markers. The expression of these markers and the change in their expression 
over baseline will be correlated with clinical response. The investigators would hypothesize 
that patients with recurrent/residual tumor will have a lower number of CD8+ cells, as well 
as a lack of PD-L1 positive immune cells at the 25 week time point. The same analysis will 
be performed in all patients with biopsies performed for suspected recurrence. 
 
The baseline expression of PD-L1 and CD8 will be correlated with the strain of BCG used 
prior to entering the trial in an exploratory fashion to determine if BCG strain affects immune 
marker expression. 
 
RNA Sequencing 
 
RNA-seq will be performed on Illumina’s TruSeq RNA Access platform for formalin-fixed, 
paraffin-embedded tissues by an external laboratory designated by Genentech/Roche, 
identical to the methods used in the Phase II atezolizumab trial. Analysis will include 
assignment of all patients to the four TCGA clusters according to the subtyping methods 
used by the investigators of the Phase II atezolizumab trial. (21) 
 
Genentech also has a proprietary signature under investigation that will be tested. (22) 
Several different previously described multi-gene immune signatures will also be tested in 
the same RNAseq dataset for their ability to predict response to atezolizumab therapy. (23) 
 
Whole exome sequencing 
 
DNA extraction:  
Sections (number and thickness to be defined based on available material) from archived 
formalin-fixed, paraffin-embedded (FFPE) tissue blocks containing tumour tissues and 
PBMC will be provided to the VPC. DNA is extracted using a Maxwell RSC instrument 
(Promega) according to manufacturer’s protocols. DNA quality and quantity are analysed 
using the TapeStation (Agilent Technologies). 
 
Whole exome library preparation: 
DNA preparation and enrichment of DNA libraries will follow the Roche SeqCap EZ 
HyperCap workflow version 2.3. Briefly, DNA is fragmented by sonication (M220 
instrument, Covaris) followed by end repair, A-tailing,  adapter ligation, clean-up and 
amplification using the KAPA HyperPrep method (KAPA BioSystems) according to the 
manufacturer’s protocol. After size selection and quantification, pools of DNA libraries (4-
plex for tumour DNA and up to 12-plex for germline DNA) are subjected to enrichment by 
liquid phase hybridization using the SeqCap EZ MedExome probe pool, amplification and 
clean-up. Quantification and enrichment rate of the captured libraries are performed by 
qPCR. 
 
 
 
Library sequencing: 
Pooled libraries are sequenced on an Illumina NextSeq500 sequencing instrument using 
a paired-end 2x150 bp protocol. The sequencing strategy is to aim for 60x and 200x 
average sequencing coverage for germline and tumour DNA, respectively.  
 


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Sequence read alignment: 
Paired-end reads are trimmed to remove adapters, and bases with a quality score <20 are 
masked. Alignment to the GRCh38.p12 reference genome is performed using BWA-MEM 
(version 0.7.15) (23); Samtools (version 1.7) (24) is used for sorting and removal of reads 
with MAPQ<20. Duplicate reads are marked and removed with Picard (version 2.18.0) 
(http://broadinstitute.github.io/picard/). Base level statistics, including depth and nucleotide 
counts, are generated using Pysamstats (https://github.com/alimanfoo/pysamstats). 
 
Identification and characterization of mutations: 
A version of the following method will be used where variant filtering is adjusted based on 
observed sequencing depth. Somatic single nucleotide variants (SNVs) and 
insertion/deletions (indels) are called when their variant allele frequency (VAF) was above 
2% with at least 10 supporting unique reads in locations with above 30× depth. Candidate 
mutations are discarded if the VAF is less than 3× that of the paired WBC or less than 20× 
the background error rate, defined as the mean VAF of the substituted base(s) across all 
WBC controls at the corresponding position(s). For variants adjacent to genomic repeats 
or regions with a strongly predominant base (>80% of local bases), we required a VAF 
>40× the background error rate. Variants are also filtered if their mean distance from the 
end of supporting reads was <6 bases. Functional annotation is performed using Annovar 
(25), and SNVs and indels identified in the Exome Aggregation Consortium (ExAC) 
database with population allele frequencies >5% are discarded. Most relevant final variants 
are manually verified in Integrative Genomics Viewer (IGV) 2.3.90 (26). 
  
Optional: putative germline variants are identified from WBC data and defined as non-
reference bases with VAFs between 30% and 70% and a minimum read depth of 40×. The 
pathogenicity of non-truncating missense variants was assessed using ClinVar annotation 
of clinical significance and/or the availability of COSMIC IDs. 
 
TruCulture 
 
The TruCultue analysis will be conducted only at designated trial sites. Only 50 patients 
will be analyzed on the trial. These sites will be contacted individually to request 
participation. 
 
We will use the TruCulture system for measurement of systemic immune response before 
and after treatment with atezolizumab. TruCulture has been developed by Myriad-Rules 
Based Medicine as a point-of-care whole blood syringe-based assay for the measurement 
of multiple cytokines in peripheral blood. We propose to use five different tubes for each 
patient assay: 1) 1 tube containing SEB for baseline systemic response; 2) 1 tube 
containing SEB and atezolizumab to test ability of atezolizumab to enhance the systemic 
response; 3) 1 tube with atezolizumab alone as a control; 4) 1 tube with BCG to test 
response after prior intravesical therapy; and 5) a null tube for negative control. The 
syringe, which is designed for integrated collection and culture, is pre-loaded with 2 mL of 
buffered media containing the selected stimulant (e.g. SEB) which can trigger a T-cell 
response (expansion/activation) and resultant cytokine production.  We will test whether 
the comparison of cytokine response in the presence and absence of atezolizumab prior 
to therapy can predict response to atezolizumab.  
 
TruCulture syringes will be sent to participating sites and maintained at -20°C until time of 
use. Before use the TruCulture tubes will be removed from the freezer and allowed to warm 
up to ambient temperature. Blood will be obtained from the antecubital vein with the syringe 
systems fitting directly into a vacutainer set. Exactly 1 mL will be drawn into each of the 
five TruCulture syringes. Within 15 minutes, the tubes will be inserted into a dry block 
incubator and maintained at 37°C for 48 hr. At the end of the incubation period, the tubes 
will be opened and a valve inserted, stopping the stimulation and partitioning the liquid 
supernatant. The tubes will be re-capped and immediately frozen at -80°C until testing. 
Sampling time points will include prior to the first dose of atezolizumab and prior to the 


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second dose of atezolizumab. In each case the blood will be drawn on the day of drug 
administration.  
 
Centralized analysis will be performed using Luminex xMAP technology in a CLIA-certified 
third party laboratory designated by Roche/Genentech. For whole blood stimulation, we 
will utilize the eighteen cytokines that have been previously defined as the core BCG 
signature. The Least Detectable Dose (LDD) for each assay will be derived by averaging 
the values obtained from 200 runs using the matrix diluent, and adding 3 standard 
deviations to the mean. The Lower Limit of Quantification (LLOQ) will be determined based 
on the standard curve for each assay.   
 
Mass Cytometry 
 
Peripheral blood will be collected in lithium heparin-coated vacutainer blood collection 
tubes. Proteomic Stabilizer 1 buffer (Smart Tube Inc) will be added to 2 ml blood in a 5 ml 
cryovial as soon as possible (within 30 minutes). After 10 minute incubation at room 
temperature, the blood will be frozen to -80°C and shipped on dry ice for central analysis 
by cytometry by time of flight (CyTOF). Blood will be drawn before the 1st, 2nd, 3rd and 5th 
doses (on day of atezolizumab administration). 
 
Samples will be thawed and red blood cells will be lysed using Smart Tube’s lysis buffer 
according to the manufacturer’s instructions. Samples will then be barcoded with a 
combination of palladium isotopes using Fluidigm’s barcoding kit, and up to 20 samples 
will be pooled and stained together using Fluidigm’s standard protocols. Barcoding 
prevents variation in staining intensity between different samples due to technical variation. 
 
Cells will be incubated with Fc block to prevent non-specific antibody binding by Fc 
receptors, and will be stained with a panel of surface markers. The cells will then be 
permeabilized and stained with a panel of antibodies specific intracellular proteins such as 
Ki67. Data will be acquired on a CyTOF2 machine (Fluidigm) at the BC Cancer Research 
Centre (affiliated with the Vancouver Prostate Centre). The staining panel will contain 
antibodies specific for a broad range of immune cells including, CD4+ and CD8+ T cells, B 
cells, dendritic cells (DC), monocytes, myeloid derived suppressor cells, natural killer (NK) 
cells, and granulocytes.  The staining panel will also include markers for deeper 
phenotyping of immune cells including, markers of T cell and antigen presenting cell 
activation and subtypes, and a panel immune checkpoints and their ligands. 
 
Genomic analysis of urine 
  
Total nucleic acid will be isolated from voided urine (30 mL) with the QIAmp total nucleic 
acid isolation kit. Nucleic acid will be sequencing adapter ligated and enriched for 90 of the 
most recurrently altered bladder cancer genes including mutations, CNV and 
translocations. Next generation sequencing will be performed on Illumina NextSeq or 
HiSeq instruments. Targeted enrichment of a focused panel of recurrently altered bladder 
cancer genes will permit very deep (>10,000x depth) sequencing allowing detection of 
genomic abnormalities as low as 0.1% abundance. Bioinformatic analysis will be 
conducted using custom designed pipeline which integrates noise suppression algorithms 
to aid in high confidence identification of mutations, copy number variation and 
translocations. Through serial urine collection and analysis we can also compare allelic 
burdens over time within individual patients. 
 
Data analysis performed by: 
 
1. 
Mike Wu, Ph.D., SWOG, will lead all data analysis. 
2. 
The biomarker team at Genentech/Roche designated external lab will assist with 
IHC analysis (lead: Sanjeev Mariathsan, Ph.D./David Shames, Ph.D.).  


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3. 
Bioinformatic assistance with RNA-seq, WES, and TruCulture analysis will be 
provided by Genentech/Roche (lead: Sanjeev Mariathsan, Ph.D./Matthew Albert, 
Ph.D.) 
4. 
Analysis of the data related to peripheral immune cells will occur at the Vancouver 
Prostate Centre under the direction of Peter Black, MD. 
5. 
Analysis of data related to cell free DNA in urine will be performed by Convergent 
Genomics under the direction of Theresa Koppie, MD and Trevor Levin, Ph.D. 
 
Who will be performing testing?   
 
1. 
PD-L1and CD8 immunohistochemistry – Genentech/Roche or in an external 
commercial laboratory designated by Genentech/Roche 
Richard Price, PhD or designate 
Corporate Headquarters 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080 
 
2. 
RNA-seq analysis – Genentech/Roche or in an external commercial laboratory 
designated by Genentech/Roche 
Richard Price, PhD or designate 
Corporate Headquarters 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080 
 
3. 
Whole exome sequencing (neoantigen load) – Genentech/Roche or in an external 
commercial laboratory designated by Genentech/Roche 
Peter Black, M.D. or the Vancouver Prostate Centre 
Corporate Headquarters 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080 
 
4. 
TruCulture analysis - Genentech/Roche or in an external commercial laboratory 
designated by Genentech/Roche 
Richard Price, PhD or designate 
Corporate Headquarters 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080 
 
5. 
Mass Cytometry – Morgan Roberts/Peter Black 
Vancouver Prostate Centre 
2660 Oak St,  
Vancouver, BC  
V6H 3Z6 
 
6. 
Analysis of cell free DNA in urine - Trevor Levin/Theresa Koppie 
Convergent Genomics 
499 Illinois St. Suite 210 
San Francisco, CA 94158 
 
 


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18.1 
References
 
1  
Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy:  a single-arm, multicentre, phase 2 trial.  Lancet 387:  
1909-1920, 2016. 
 
2  
Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical 
activity in metastatic bladder cancer. Nature 515:558-62, 2014. 
 
3  
Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy:  a single-arm, multicentre, phase 2 trial.  Lancet 387:  
1909-1920, 2016. 
 
4  
Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy:  a single-arm, multicentre, phase 2 trial.  Lancet 387:  
1909-1920, 2016. 
 
5  
Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting 
adaptive immune resistance. Nature 515:568-71, 2014. 
 
6  
Gunes G, Mendoza-Rodriguez M, Baras A, et al. Journal of Urology, Vol. 193, No. 4S, 
Supplement, Monday, e723, 2015. 
 
7  
Ribas A, Robert C, Hodi FS, et al. J. Clin. Oncol. 33, 2015 suppl. abstract 3001, 2015. 
 
8  
Zaretsky JM, Garcia-Diaz A, Shin DS, et al.  Mutations associated with acquired resistance 
to PD-1 Blockade in Melanoma.  N Engl J Med 375(9):  819-829, 2016. 
 
9  
Gunes G, Mendoza-Rodriguez M, Baras A, et al. Journal of Urology, Vol. 193, No. 4S, 
Supplement, Monday, e723, 2015. 
 
10  
Ribas A, Robert C, Hodi FS, et al. J. Clin. Oncol. 33, 2015 suppl. abstract 3001, 2015. 
 
11  
Schumacher TN, Schreiber RD: Neoantigens in cancer immunotherapy. Science 348:69-
74, 2015. 
 
12  
Cuka N, Hempel H, Sfanos K, et al. PIP: An Open Source Framework for Multithreaded 
Image Analysis of Whole Slide Images. Laboratory Investigation; 94:398A-A, 2014. 
 
13  
Le DT, Uram JN, Wang H, et al.  PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency.  N Engl J Med 372(26):2509-20, 2015. 
 
14  
Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124-8, 
2015. 
 
15  
Romano E et al, PNAS 2015, (doi: 10.1073/pnas.1417320112) PMID: 25918390 Ku GY et 
al, Cancer, (doi: 10.1002/cncr.24951) PMID: 20143434, 2010. 
 
16  
Huang AC, et al. Nature, doi:10.1038/nature22079 PMID: 28397821, 2017. 
 
 


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17  
Bishop JL, et al, Oncotarget, doi: 10.18632/oncotarget.2703 PMID: 25428917, 2015. 
 
 
18  
Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical 
activity in metastatic bladder cancer. Nature 515:558-62, 2014. 
 
19  
Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy:  a single-arm, multicentre, phase 2 trial.  Lancet 387:  
1909-1920, 2016. 
 
20  
Cuka N, Hempel H, Sfanos K, et al. PIP: An Open Source Framework for Multithreaded 
Image Analysis of Whole Slide Images. Laboratory Investigation; 94:398A-A, 2014. 
 
21  
Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy:  a single-arm, multicentre, phase 2 trial.  Lancet 387:  
1909-1920, 2016. 
 
22  
Gettinger S, Kowanetz M, Koeppen H, et al. J Clin Oncol 33, (suppl; abstr 3015), 2015. 
 
23  
Ribas A, Robert C, Hodi FS, et al. J. Clin. Oncol. 33, 2015 suppl. abstract 3001, 2015. 
 
 
 


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18.2 
Specimen Banking and Translational Medicine Material Instructions for SWOG 
Biospecimen Bank (BB) 
 
The Bank will provide kits for collection of blood for mass cytometry to sites via the Kit 
Management Application. The kits will include the Proteomic Stabilizer 1 buffer (Smart 
Tube Inc) in a 5 ml cryovial. Sites will provide all other collection and processing supplies.   
 
The Bank will receive FFPE tissue specimens (slides and scrolls or block); frozen whole 
blood collected in sodium citrate, frozen whole blood processed with Proteomic Stabilizer 
1 buffer (PROT1) for mass cytometry, frozen whole blood collected in TruCulture tubes, 
and frozen urine. 
 
Upon receipt, the Bank will accession, barcode, and store the FFPE tissue 
scrolls/slides/blocks at room temperature.  H&E slides received for central pathology 
eligibility review will be scanned to a virtual image and sent to Dr. M. Scott Lucia via the 
Virtual Imaging for Pathology, Education & Research (VIPER) application system.  
 
The SWOG Statistics and Data Management Center will provide a list of cases and number 
of slides that the Bank will prepare to distribute in batches throughout the study to Dr. Price 
(or designee) at Genentech for PD-L1 and CD8 immunohistochemistry staining, as well as 
RNAseq analysis.   
 
Richard Price, Ph.D. 
Corporate Headquarters 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080 
 
Upon receipt, the Bank will accession, barcode, and store the 5 mL frozen blood in sodium 
citrate tubes in a -80°C freezer.  The bank will send these samples to Vancouver at the 
end of the study.  
 
Upon receipt, the Bank will accession, barcode, and store the TruCulture tubes in a -80°C 
freezer. The bank will send these to Genentech once 50 patient samples have been 
collected.   
 
Upon receipt, the Bank will accession, barcode, and store the 5 mL cryovials of blood in 
PROT1 buffer for mass cytometry in a -80°C freezer. The bank will send these samples to 
Vancouver at the end of the study. 
 
Upon receipt, the Bank will accession, barcode, and store the frozen urine in a -80°C 
freezer. The bank will send these samples to Convergent Genomics at the end of the study. 
 
 
 


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18.3 
Quality Assurance Auditing and Monitoring 
 
The Quality Assurance Program of the Groups participating in the NCTN was developed 
to enhance the reliability and validity of clinical trials data through the use of routine 
monitoring procedures which includes auditing as one component.  The purpose of an audit 
is to document the accuracy of data submitted to the SWOG Statistics and Data 
Management Data Operations Center and to verify compliance with protocol and regulatory 
requirements.  The program also surveys data management practices at each institution in 
order to provide educational support to the sites regarding issues related to data quality, 
data management, and other aspects of quality assurance. 
 
Audits are conducted according to FDA regulations and NCI guidelines for Auditing Clinical 
Trials for the National Clinical Trials Network (NCTN) Program, NCI Community Oncology 
Research Program (NCORP) and Research Bases: 
http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ctmbauditguidelines.pdf. 
 
Each institution is audited at least once every three years, but remains at annual risk of an 
audit.  Routine monitoring of Institutional Performance Review reports and timeliness of 
reporting of Serious Adverse Events is conducted to identify institutions that may require 
more frequent audits. 
 
The audit team consists of qualified individuals capable of providing a medical assessment 
of the patient cases (Quality Assurance staff, physician, nurse or experienced clinical 
research associate [CRA]).  A number of patients equal to 10% of the accrual since the 
last audit with a minimum of three are randomly selected for review at each institution.  In 
addition, a limited review of eligibility and consent only is conducted for at least one 
unannounced case at each on site audit. 
 
The major objective of the audit process is to verify study data that could affect the 
interpretation of primary study endpoints.  This is done through independent verification of 
study data against the source documents.  Primary source documentation reviewed during 
an audit includes the following: research records, hospital charts, clinic charts, lab reports, 
x-rays, scans, radiotherapy reports, operative reports, pathology reports and other special 
studies required by protocol. 
 
By comparing the data collection forms submitted to the SWOG Statistics and Data 
Management Center with the primary records and referring to the protocol, the audit team 
reviews the records to determine compliance with protocol requirements for eligibility, 
treatment administration, response assessment, toxicity reporting and general data quality. 
Auditors verify that the current IRB-approved version of the consent form was signed prior 
to registration and that subjects were informed of new findings that could affect their 
willingness to participate in the study.   NCTN investigators and institutions are expected 
to follow the protocol and lead Group policies in treating patients registered on Group 
protocols.  Among other requirements, investigators/institutions must follow SWOG's 
policies for dosing principles, reporting of Serious Adverse Events, and follow-up of all 
patients.  
 
The audit team also verifies that the protocol and its amendments received initial and 
continuing IRB review and approval and that safety reports and serious adverse events 
were submitted to the IRB.  Investigational drug accountability record forms (DARFs) are 
reviewed and random patients are cross referenced against the medical record.  A tour of 
the pharmacy is conducted to verify security and storage conditions as well as the physical 
inventory. 
 
The audit report is comprised of three components: 1) conformance to IRB and informed 
consent requirements, 2) the pharmacy and use of NCI DARFs, and 3) patient case review.  
An acceptable rating requires no deficiencies, few lesser deficiencies, or major deficiencies 
that were addressed prior to the audit.  Institutions found to be "unacceptable" or 


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"acceptable, but requires “follow-up” on any component are required to submit a written 
response and/or corrective and preventative (CAPA) action plan.  Failure to submit a 
written response including a corrective and preventative action plan within the required 
timeframe will result in suspension of registration privileges.  A re-audit of any component 
rated as unacceptable will be conducted within one year after the unacceptable audit.  An 
unacceptable rating for the same audit component on two consecutive audits will result in 
probation.  Accrual will be suspended pending submission of a site improvement plan that 
addresses key infrastructural issues contributing to poor performance.  An unacceptable 
rating at the second re-audit may result in termination from the group.  If systematic 
misrepresentation of data is identified, an immediate repeat audit is scheduled by the 
representatives from the Group with the NCI and/or the FDA present. 
 
In some cases, non-compliance for issues such as timeliness of data submission, SAE 
reporting and submission of specimens is monitored off site rather than scheduling a re-
audit.  Failure to show improvement may result in scheduling of a re-audit or other 
disciplinary action. 
 
Results of all Quality Assurance Audits are entered into the CTMB-AIS database and 
reported to the NCI, the Principal Investigator of the institution that was audited, and group 
leadership.  Protocol specific audit results are also sent to the Statistics and Data 
Management Center to inform the statisticians, data chairs and study chairs of any 
significant discrepancies involving eligibility, treatment, toxicity or response assessment. 
 
The Quality Assurance Program performs their educational role through several 
mechanisms including presentations during the Group Meetings, online Clinical Trials 
Training Courses, collaboration with others such as the Pharmacy Committee and 
Statistics and Data Management Center to develop training tools, and memos and 
newsletter articles that are distributed to all Group institutions to educate research staff 
about changes in regulatory and quality assurance issues and audit procedures. 
 
Additional Monitoring 
 
In addition to the standard auditing process outlined above, the following additional 
requirements will be implemented for this study: 
• 
Routine monitoring by Data Coordinators at the Statistics and Data Management 
Center.   
• 
Risk-based monitoring by Monitors at the Statistics and Data Management 
Center.   
• 
Additional on-site monitoring visits by Quality Assurance Auditors at the 
Operations Office.  
 
a. 
Routine Monitoring at the SWOG Statistics and Data Management Center 
 
Data Coordinators at the SWOG Statistics and Data Management Center 
(SDMC) will perform routine monitoring with the following actions: 
 
Monitor data quality through routine review of submitted data such as on-study, 
baseline and follow up tumor assessment, lab, treatment, off treatment, and follow 
up case report forms to identify and follow-up on missing data, inconsistent data, 
data outliers, and potential protocol deviations that may be indicative of systemic 
or significant errors in data collection and reporting at a site. 
 
Analyze site characteristics, performance metrics and clinical data to identify trial 
sites with characteristics correlated with poor performance or noncompliance 
through the SWOG Institutional Performance Reporting mechanism and other 
available reports. 


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• 
Verify critical source data remotely via the collection and review of 
pathology, radiology and applicable lab reports.  This includes the review 
and confirmation of appropriate disease classification as determined by 
the pathology report, and assessment of response to treatment based on 
scan reports uploaded to the Electronic Data Capture (EDC) system and 
submitted follow-up disease assessment forms.  
• 
To assure data are as consistent, complete and accurate as possible, all 
subject data must undergo careful review by Data Coordinators (DCs).  
After verifying that all data forms required to determine eligibility have been 
received or at a time point designated when all the required forms should 
have been received, the DC reviews the data and completes an initial 
evaluation. 
 
The initial review includes the following: 
 
• 
Determine that all required data fields on each form were completed and 
are consistent with other data. 
• 
Determine if all prestudy tests and exams were performed within protocol 
specified time limits. 
• 
Determine if each eligibility criterion was met and properly documented. 
• 
Review and confirm pathology based on the pathology report uploaded to 
the EDC system. 
• 
Verify that stratification and/or descriptive factors (if applicable) were 
correctly identified at registration. 
• 
Verify that the subject received the assigned study treatment and correct 
dose(s). 
• 
Verify that the treatment was started within the time limit indicated in the 
protocol (if applicable). 
• 
Determine if adverse events reported are consistent with other data and 
entered as required by study specifications. 
• 
Post internal notes to add additional information which may be useful to 
the study sponsor, monitors, or statisticians, but which do not require 
action by site personnel. 
• 
Use the query tool to request additional data classifications and 
corrections of the CRA. 
 
The DC will perform subsequent review of data when new data become available 
or queries are answered.  Regular review will also occur while patients are still on-
study, at the time of progression, once they are removed from study and at the 
time of death. 
 
Subsequent reviews include the following: 
 
• 
Determine if all required data fields on each newly submitted form were 
completed and consistent with other data. 
• 
Evaluate all new treatment documentation for correct treatment and dose. 
• 
Conduct assessment of response to treatment based on scan reports 
uploaded to the EDC and submitted disease assessment forms. 
• 
Review and code any new concomitant medications as required by study 
specifications. 
• 
Evaluate if the subject is or should be off protocol treatment per protocol 
criteria. 
• 
Review and evaluate death if death of subject is reported. 
• 
Use the query tool to request additional data classifications and 
corrections. 


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• 
Post internal query notes to add additional information that may be useful 
to the study sponsor, monitor, or statisticians but which do not require 
action by site personnel. 
• 
Review site responses to the queries and the corrected or amended eCRF 
pages.  When corrections and responses are considered satisfactory, 
queries are closed by the data coordinators.  Unsatisfactory responses are 
re-queried and tracked. 
• 
Perform re-evaluations promptly after responses to queries are received. 
 
b. 
Centralized Risk-based Monitoring at the Statistics and Data Management Center 
(SDMC)  
 
Monitors at the Statistics and Data Management Center (SDMC) will support the 
risk based monitoring approach for this trial with the following actions: 
 
Off-site monitoring to include auditable elements through administration of the 
second course of treatment and Weeks 13 and 25 disease assessment for the first 
two patients registered at each site where an onsite audit has not yet occurred.  
 
For instructions for uploading documents in the SDP see protocol section 18.3d. 
Documents required: 
• 
Eligibility: Informed Consent title page, signature page and responses to 
Future Contact and Samples for Future Research Studies, S1605 
Eligibility Criteria form,  , source documents to support the following:  
Onstudy labs, H&P, baseline AEs, ECG, Baseline Prior Treatment form 
 
• 
Cycle 1: AE/SAE, and treatment records, source document for pulmonary 
signs and symptoms 
 
• 
Cycle 2: Week 7 labs, AE/SAE, treatment records, source document for 
pulmonary signs and symptoms 
 
 
Please note: 
• 
The S1605 Registration Worksheet and S1605 Eligibility Criteria form 
must be signed and dated by the PI 
• 
Baseline Onstudy labs must be within 42 days prior to Registration 
• 
Treatment records must include physician orders and administration 
records/logs including reasons for dose modifications 
 
 
c. 
Onsite Monitoring 
 
• 
Additional on-site monitoring visits with the first site visit within 6 months 
of first 
• 
patient registration. 
• 
Monitoring visits will be combined with other routine audits whenever 
possible. The initial monitoring visit may be postponed up to 3 months to 
coincide with a routine audit or to coincide with a routine audit of another 
institution in the same geographic area. Monitoring visits may also be 
postponed if no accrual or activity has occurred beyond the timeframe 
covered by the off-site central monitoring. 
• 
Subsequent monitoring visits will be conducted according the following 
criteria: 
• 
If > 5 patients per year (~ 10% of sites) – annually 
• 
< 5 patients per year – semiannually 


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• 
More frequent monitoring visits to a site may be scheduled in response to 
several factors – high rate of accrual, unacceptable monitoring visit results, 
centralized electronic monitoring outcome, turnover in staff, etc.   
• 
All sites that receive and dispense investigational agents must be 
monitored on site to allow at least one visit to the pharmacy with the 
following exceptions: 
o 
Sites that use a centralized pharmacy may be monitored 
at this central location. 
o 
After an initial onsite visit, NCORP sites and LAPS/Main Member 
Affiliates may be monitored at a central location. 
o 
Pharmacies monitored during SWOG site visits for other studies 
will suffice for the onsite monitoring requirement. 
o 
The need for subsequent onsite visits will be determined on a 
case by case basis including past audit results, number of 
patients on the investigational agent, etc. 
 
Communication of Monitoring Results 
 
The monitoring team will meet routinely to share all aspects of monitoring (on site, 
centralized, safety, for-cause).  When needed, the SWOG Executive Officer for 
Quality Assurance will be consulted. 
 
All monitoring visits results will be reported according to NCI-CTMB requirements 
via the CTMB-AIS data base and regularly reviewed by SWOG monitoring staff. 
 
Summarized results of all monitoring visits will be provided semi-annually to the 
SWOG Board of Governors and the study team. Any problems or issues of concern 
will be reported to the Data and Safety Monitoring Committee on an as-needed 
basis. 
 
Safety Specific Centralized Monitoring at the Operations Office 
 
Each Serious Adverse Event (SAE) report submitted (via CTEP-AERS) will be 
reviewed by the SWOG SAE Coordinator.  Supporting documentation for any 
deaths on study will be requested and compiled with the report and sent to the 
Physician Reviewer.  As mentioned below all sites will undergo mandatory training 
and this will include training regarding SAE reporting.  SWOG regularly monitors 
timeliness of SAE reporting and addresses any issues of poor performance with 
individual sites. 
 
The study will be monitored for under reporting/missed Serious Adverse 
Events:  The SWOG SAE Coordinator receives a weekly report from the data base 
that includes all adverse events that are submitted through routine submission that 
potentially also meet expedited reporting criteria but for which no CTEP-AERS 
report is found.  The Coordinator is responsible for following up with the 
responsible site to ensure that SAEs are not missed/under-reported. 
 
The study will be monitored for trends in Serious Adverse Events:  A “new 
SAE on study” report is generated each time a new Serious Adverse Event is 
entered into the SWOG data base.  It is a cumulative report that lists all SAEs 
reported for the protocol.  This allows those who review the report to identify 
concerning trends in reported events; events that may be occurring at greater 
intensity (higher toxicity grade) or frequency than expected.  The SAE Coordinator, 
Physician Reviewer, Study Chair, and assigned Statisticians are responsible for 
regularly monitoring this repo 
 
Additional Approaches to be Used 


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• 
Mandatory training of key site personnel prior to first patient registration. 
• 
Timely review of all monitoring reports to identify sites that require 
additional training, monitoring, disciplinary action, etc. 
• 
Mentoring visits and additional communication between monitor and site 
staff to assess potential problem areas, provide feedback on data 
submission quality and timeliness, identify staff turnover, etc. 
• 
Additional mandatory centralized training to be provided to all sites if major 
changes to the protocol occur or common problem areas are identified. 
 
Management of Noncompliance 
 
Issues of particular concern related to patient safety and questions of site fraud will 
be managed according to SWOG standard policies and the policies of the NCI 
CTMB for auditing of clinical trials under the NCI National Clinical Trials Network 
(NCTN) Program. 
 
Where important deviations are discovered, additional site training components 
will be developed and implemented. 
 
As with standard NCTN procedures, sites will be required to develop and 
implement corrective action plans in response to any deficiencies identified at a 
monitoring visit. 
 
Ensuring Quality Monitoring 
 
All staff involved in monitoring are required to undergo training in the principles of 
clinical investigations and human subjects protection.  They are also required to 
complete the same protocol specific training required of the site staff. 
 
All monitoring and auditing processes for the study will be reviewed by study 
leadership twice per year to ensure conformance to the monitoring plan. 
 
Monitoring Plan Amendments 
 
At each formal review of the monitoring plan and conformance to it, the study 
leadership will make a recommendation regarding the need for amendments to the 
monitoring plan.  These amendments will be reviewed and approved by the NCI 
and provided in this protocol section and will be submitted to the FDA. 
 
d. 
Instructions for Uploading Source Documents for the Off Site Centralized 
Monitoring Review by Statistics and Data Management Center (SDMC) Monitors 
 
Per protocol Section 18.3, a source document review is to be conducted by SDMC 
monitors for the first 2 patients registered to treatment at each study site where an 
onsite audit has not yet occurred.  The SDMC monitor will notify the head CRA 
within 5 weeks of registration of the upcoming review. This will allow ample time to 
begin uploading source documents through the first two courses of treatment and 
first two disease assessment timepoints.  All source documents will be uploaded 
to the Source Document Portal (SDP) which can be accessed directly through 
CTSU.org by going to the Auditing and Monitoring tab and selecting Source 
Document Portal. The SDP can also be accessed through Medidata Rave.  
 
Sites will use the SDP to upload source documents to confirm eligibility and 
activities for Cycles 1 and 2 and for the Weeks 13 and 25 Disease Assessments. 
 
Documents required: 


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• 
Eligibility: Informed Consent title page, signature page and responses to 
Future Contact and Samples for Future Research Studies. S1605 
Eligibility Criteria form and S1605 Registration Worksheet must be signed 
by the Registering Investigator, source documents so support the Onstudy 
labs, H&P, source document for baseline AEs, ECG, and source 
documents to support Baseline Prior Treatment form 
• 
Cycle 1: AE/SAE, and treatment records, source document for pulmonary 
signs and symptoms 
• 
Cycle 2: Week 7 labs, AE/SAE, treatment records, source document for 
pulmonary signs and symptoms 
 
Please note: 
• 
The S1605 Eligibility Criteria form and S1605 Registration Worksheet 
must be signed and dated by the Registering Investigator 
• 
Baseline Onstudy labs must be within 42 days prior to Registration 
• 
Treatment records must include physician orders and administration 
records/logs including reasons for dose modifications 
 
The SDP in CTSU provides a tool to redact PHI. Please ensure all source 
documents are properly and completely redacted and free of PHI.   
 
CTSU recommends that users complete the training “CTSU Central Monitoring 
Using the Source Document Portal (SDP)” which is posted on the CTSU website 
under Resources -> Educational Multimedia -> Webinars. 
 
For 
questions 
regarding 
the 
SDMC 
monitoring 
please 
contact 
centralmonitorquestion@crab.org 


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18.4 
S1605 Pre-Registration Study Chair Approval Form 
 
 


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18.5 
Investigator Electronic Signature 
 
S1605 requires an investigator to sign off on the data for each patient. This will be done 
within Rave using an electronic signature. The treating investigator may sign off on their 
own patient(s), or the site PI may sign for all S1605 patients at their site. The person who 
signs will be held responsible for the accuracy and completeness of ALL submitted data. 
 
Note: The investigator must be assigned to the Rave Investigator task on the site 
Delegation of Task Log (DTL) prior to completing the e-signature(s). If they are not 
assigned on the DTL, they will not have Rave access to this study. If you have questions 
about the DTL or the signing process, please contact gu@crab.org.   
 
Investigator Instructions for Completing the e-Signature in iMedidata  
 
When you first login to iMedidata, there will be a list of studies that you have been given 
access to in the middle of the page. Use the search bar to find “S1605” and select the link 
for “Rave EDC”:  
 
The signature should be done using the “Site Investigator” role. If you have more than one 
role on your account, be sure to select “Site Investigator” from the Role Selection drop 
down when you log in. 
 
After entering the EDC, there will be a list of sites that you currently have access to. You 
can either select the site to view a list of patients for that site or you can use the search bar 
at the top to look up a specific patient. Change the dropdown to “Subject” and typing the 
ID in the search bar. You can also view a complete list of patients that you have access to 
by selecting “Subject” from the drop down and clicking on the search icon with the search 
bar blank  
 
After you have selected a patient, the list of available folders will be on the left side of the 
page. The very first folder on the list will be titled “Electronic Signature Page”. Clicking 
on that folder will open up the Electronic Signature Page form.  
 
The following steps will be required to sign off on the data for each patient: 
• 
Review the data that has been submitted up through the clinical cutoff date 
specified on the Electronic Signature form.  
Other folders and forms can be accessed using the menu on the left side of the 
patient’s homepage as above.  
• 
Once you are ready to sign, check the box on the form and select “Sign and 
Save”.  
• 
You will be prompted to enter your iMedidata username and password as an 
electronic signature. This is the same username and password that you used to 
login originally. Then select “eSign”.  
• 
You will then be directed back to the Electronic Signature Page with two 
confirmations of the signature - a yellow banner at the top and a blue banner at the 
bottom specifying who signed and the time stamp.  
• 
Repeat these steps for all applicable patients on your list.  
 
 

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