Conditions: Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall Infiltrating Renal Pelvis and Ureter Urothelial Carcinoma Stage II Bladder Cancer AJCC v8
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
This phase II trial studies the effect of avelumab, gemcitabine and carboplatin before surgery compared with surgery alone in treating patients with muscle invasive bladder or upper urinary tract cancer who are not able to receive cisplatin therapy. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving avelumab together with gemcitabine and carboplatin before surgery may work better in lowering the chance of muscle invasive urinary tract cancer growing or spreading, in patients who cannot receive cisplatin therapy compared to surgery alone.

Detailed description:
PRIMARY OBJECTIVE:

I. To compare pathologic complete response (pCR, pT0N0) with avelumab plus gemcitabine and carboplatin (AGCa) versus (vs.) no neoadjuvant therapy preceding protocol surgery for muscle-invasive bladder cancer or upper tract urothelial carcinoma (MIBC/UTUC) for participants who are ineligible for cisplatin-based chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate toxicities with AGCa, and to compare resectability rates and surgical complications by arm in this population.

II. To compare event-free survival (EFS) with AGCa versus no neoadjuvant therapy in this population.

III. To compare overall survival (OS) with AGCa versus no neoadjuvant therapy preceding surgery in this population.

IV. To compare pathologic complete response (pCR, pT0N0) with avelumab plus gemcitabine and carboplatin (AGCa) vs. no neoadjuvant therapy preceding protocol surgery in the subset of participants who received at least 2 cycles of neoadjuvant therapy in Arm A.

BANKING OBJECTIVE:

I. To bank tumor tissue, blood, and urine for future correlative genomic, transcriptomic, and proteomic studies to discover molecular signatures associated with pCR and resistance.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive avelumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up 4 in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after final systemic therapy, patients undergo standard of care surgery.

ARM B: Patients undergo standard of care surgery.

After completion of study treatment, patients are followed up every 12 weeks for years 1-2, every 6 months for year 3, then annually in years 4-5.

Arms:
arm 1: Patients receive avelumab IV over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up 4 in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after final systemic therapy, patients undergo standard of care surgery. arm 2: Patients undergo standard of care surgery.

Interventions: intervention 1: Therapeutic Conventional Surgery intervention 2: Avelumab intervention 3: Gemcitabine Hydrochloride intervention 4: Carboplatin
Intervention descriptions: intervention 1: Undergo surgery intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV

Protocol document:
Prot_SAP_000.pdf: 
S2011 
 
 
Page 1 
Version Date 03/09/2023 
 
PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG CANCER RESEARCH NETWORK 
TITLE 
RANDOMIZED PHASE II TRIAL OF GEMCITABINE, AVELUMAB AND CARBOPLATIN VS. NO 
NEOADJUVANT THERAPY PRECEDING SURGERY FOR CISPLATIN-INELIGIBLE MUSCLE-
INVASIVE UROTHELIAL CARCINOMA: SWOG GAP TRIAL  
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by 
the National Cancer Institute (NCI). The trial will be led by SWOG with the participation of the 
network of NCTN organizations: Alliance for Clinical Trials in Oncology; ECOG-ACRIN Cancer 
Research Group; and NRG. 
 
Additional site requirements include completion of a protocol specific Delegation of Task Log 
(DTL) (see Section 13.4e) 
 
NCT# 04871529  
 
 
STUDY CHAIRS: 
 
Guru P. Sonpavde, M.D. 
Genitourinary Oncology Director 
Christopher K. Glanz Chair for Bladder Cancer 
Research 
Assistant Director Phase I Clinical Research Unit 
AdventHealth Cancer Institute 
University of Central Florida 
2501 N orange Ave, Ste 689 
Orlando FL 32804 
Phone:  407/303-2024 
Fax:  407/303-2038 
E-mail: Guru.Sonpavde.MD@AdventHealth.com  
 
Michael A. Liss, M.D. (Urology) 
UTHSCSA 
Dept of Urology 
7703 Floyd Curl Dr, MC 7845 
San Antonio TX 78229-3900 
Phone: 210/567-1100 
Fax:  210/567-6868 
Email:  liss@uthscsa.edu 
 
Seth P. Lerner, M.D. (Urology) 
Baylor College of Medicine 
Scott Dept of Urology 
7200 Cambridge 
Houston, TX 77030 
Phone: 713/798-6841 
Fax: 713/798-5553 
Email: slerner@bcm.edu 
 
Daniel P. Petrylak, M.D. (Oncology) 
Yale University Cancer Center 
333 Cedar Street 
FMP-313 Box 208028 
AGENTS:
 
Commercially Available Agents: 
 
Gemcitabine (Gemzar®) (NSC-613327)           
Carboplatin (CBDCA) (NSC-241240) 
 
SWOG-Held IND Agents: 
 
Avelumab (MSB0010718C; Bavencio)  
(NSC-799232) (IND-156359) 
 
BIOSTATISTICIANS: 
 
Melissa Plets, M.S. (Biostatistics) 
Cathy M. Tangen, Dr.P.H (Biostatistics) 
SWOG Statistics and Data Management Center 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue North, M3-C102 
P.O. Box 19024 
Seattle, WA 98109-1024 
Phone:  206/667-4623 
FAX:  206/667-4408 
E-mail:  mplets@fredhutch.org 
E-mail:  ctangen@fredhutch.org 
 
TRANSLATIONAL CHAIR: 
 
Joshua Meeks, M.D., Ph.D.  
Northwestern University 
675 N. S. Clair St., Suite 20-150 
Chicago, IL 60611 
Phone: 312/695-8146 
Fax: 312/695-7030 
Email: joshua.meeks@northwestern.edu 
 
 


S2011 
 
 
Page 2 
Version Date 03/09/2023 
 
 
New Haven, CT 06520 
Phone: 203/737-8076 
Email: daniel.petrylak@yale.edu 
 
 
 
 
ALLIANCE CHAMPION:   
 
Shilpa Gupta, M.D. 
Cleveland Clinic Foundation  
9500 Euclid Ave, CA-6 
Cleveland, OH 44195 
Phone: 216/444-8311 
Fax: 216/444-9464 
Email: guptas5@ccf.org 
 
ECOG CHAMPION:   
 
Suzanne Cole, M.D. 
UT Southwestern Simmons Cancer Center 
Richardson Plano 
3030 Waterview Pkwy 
Richardson, Texas 75080 
Phone: 972/669-7077 
Fax: 972/669-7190 
Email: Suzanne.cole@utsouthwestern.edu 
 
 
NRG CHAMPION:   
 
Rana R. McKay, M.D. 
UC San Diego Moores Cancer Ctr 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
Phone: 858/822-6185 
Fax: 858/822-6220 
Email: rmckay@ucsd.edu 
 
 
 
 
 
 
 
PARTICIPANTS 
U.S.-Only Participants: 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG Cancer Research Network 
 
 
 


S2011 
 
 
Page 3 
Version Date 03/09/2023 
 
 
TABLE OF CONTENTS 
 
TITLE ………………………………………………………………………………………………………………..1 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 8 
1.1 
Primary Objective ............................................................................................................................. 8 
1.2 
Secondary Objective(s) .................................................................................................................... 8 
1.3 
Banking Objectives .......................................................................................................................... 8 
2.0 
BACKGROUND ............................................................................................................................... 8 
2.1 
Neoadjuvant Therapy for Bladder Cancer: Knowledge Gap and Unmet Clinical Need in the 
Setting of Cisplatin-Ineligible Patients .............................................................................................. 8 
2.2 
Activity of Single Agent PD1/L1 Inhibitors in Urothelial Carcinoma ................................................. 9 
2.3 
Activity of PD1/L1 Inhibitors in Combination with Platinum-Based Chemotherapy for Urothelial 
Carcinoma ........................................................................................................................................ 9 
2.4 
Rationale to Support the Development of Neoadjuvant Avelumab in Combination with 
Gemcitabine and Carboplatin for Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma ....... 10 
2.5 
Inclusion of Women and Minorities and Planned Enrollment Report ............................................ 11 
3.0 
DRUG INFORMATION .................................................................................................................. 12 
3.1 
Avelumab (MSB0010718C; Bavencio) (NSC-799232, IND-156359) .......................................... 12 
3.2 
Gemcitabine hydrochloride (Gemzar®) (NSC-613327) ................................................................. 17 
3.3 
Carboplatin (CBDCA) (NSC-241240) ............................................................................................ 20 
4.0 
STAGING CRITERIA ..................................................................................................................... 20 
4.1 
Staging Criteria (AJCC, Eighth Edition) ......................................................................................... 20 
4.2 
Method of staging ........................................................................................................................... 21 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 21 
5.1 
Disease Related Criteria ................................................................................................................ 21 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 22 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 22 
5.4 
Specimen Submission Criteria ....................................................................................................... 25 
5.5 
Regulatory Criteria ......................................................................................................................... 25 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 25 
7.0 
TREATMENT PLAN ...................................................................................................................... 25 
7.1 
Treatment ....................................................................................................................................... 25 
7.2 
Disease/Recurrence Assessment .................................................................................................. 27 
7.3 
DMU Demography monitoring and enrolling patients via OPEN ................................................... 27 
7.4 
Criteria for Removal from Protocol Treatment ............................................................................... 28 
7.5 
Discontinuation of Treatment ......................................................................................................... 29 
7.6 
Follow-Up Period ............................................................................................................................ 29 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 29 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 29 
8.2 
General Considerations ................................................................................................................. 29 
8.3 
Dose Modifications and Delays ...................................................................................................... 30 
8.4 
White blood Cell Growth Factors ................................................................................................... 31 
8.5 
Dose Modification Contacts ........................................................................................................... 31 
8.6 
Adverse Event/Serious Adverse Event Reporting Guidance ......................................................... 31 
8.7 
Adverse Events Related to COVID-19 ........................................................................................... 32 
8.8 
Serious Adverse Event Reporting Requirements .......................................................................... 33 
9.0 
STUDY CALENDAR ...................................................................................................................... 38 
9.1 
Arm A:  Gemcitabine + Carboplatin + Avelumab + Surgery .......................................................... 38 
9.2 
Arm B:  Surgery Only ..................................................................................................................... 40 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................................................. 42 
10.1 
Pathologic complete remission ...................................................................................................... 42 
10.2 
Event-free Survival (EFS) .............................................................................................................. 42 
10.3 
Recurrence ..................................................................................................................................... 42 
10.4 
Performance Status:  Participants will be graded according to the Zubrod performance status 
scale. .............................................................................................................................................. 42 


S2011 
 
 
Page 4 
Version Date 03/09/2023 
 
 
10.5 
Dose Limiting Toxicities (DTLs) ...................................................................................................... 43 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 43 
11.1  
Estimate of Sample Size and Accrual Rate ................................................................................... 43 
11.2  
Analysis Plan .................................................................................................................................. 44 
11.3  
Adverse Event Monitoring .............................................................................................................. 45 
11.4 
Data and Safety Monitoring Committee ......................................................................................... 45 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 45 
There is no discipline review for this study. ................................................................................................ 45 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 45 
13.1 
Registration Timing ........................................................................................................................ 45 
13.2 
Investigator/Site Registration ......................................................................................................... 45 
13.3 
CTEP Registration Procedures ...................................................................................................... 45 
13.4 
CTSU Registration Procedures ...................................................................................................... 46 
13.5 
Oncology Patient Enrollment Network (OPEN) Registration Requirements .................................. 48 
13.6 
Exceptions to SWOG registration policies will not be permitted. ................................................... 49 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 49 
14.1 
Data Submission Requirement ...................................................................................................... 49 
14.2 
Master Forms ................................................................................................................................. 49 
14.3 
Data Submission Procedures ........................................................................................................ 50 
14.4 
Data Submission Overview and Timepoints .................................................................................. 51 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 55 
15.1 
Specimens for Banking (REQUIRED with Participant Consent) ................................................ 55 
15.2 
SHIPPING SAMPLES .................................................................................................................... 56 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 57 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 59 
18.0 
APPENDIX ..................................................................................................................................... 65 
18.1 
New York Heart Association Functional Classification ................................................................... 66 
18.2 
Patient Clinical Trial Wallet Card .................................................................................................... 66 
18.3 
Instructions for BioSpecimen bank ................................................................................................ 67 
 
 
 


S2011 
 
 
Page 5 
Version Date 03/09/2023 
 
 
PROTOCOL CONTACT INFORMATION 
 
Patient Advocate 
 
Rick Bangs 
E-mail: chezrick@comcast.net or Phone: 585/563-6561 
 
Eligibility, RAVE, Data Submission: 
 
SWOG Statistics and Data Management Center  
E-mail: guquestion@crab.org or Phone: 206/652-2267 
 
Regulatory, Protocol, Informed Consent: 
 
SWOG Operations Office 
E-mail: protocols@swog.org or Phone: 210/614-8808 
 
Medical Queries (treatment or toxicity related 
questions): 
 
Email: gurup_sonpavde@dfci.harvard.eduor call: 
Dr. Sonpavde at Phone: 617/632-2429  
 
Investigational Drug questions: 
 
See Protocol Section 3.0 orcontact the SWOG 
Operations Office at protocols@swog.org mailto: 
 
Requests for Investigator’s Brochures: 
 
See Protocol Section 3.0 or contact the SWOG 
Operations Office at protocols@swog.org  
 
Specimen Tracking System (STS) 
Amendments, Errors, Connectivity Issues 
and Technical issues with the SWOG CRA 
Workbench: 
technicalquestion@crab.org 
Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-
IAM) 
 
To review CTEP-IAM account (new requests, reset 
passwords): 
https://ctepcore.nci.nih.gov/iam/index.jsp 
 
Access to iMedidata Rave or Delegation of 
Task Log (DTL) 
 
See Protocol Section 14.1 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
 
Questions related to: 
Oncology Patient Enrollment Network 
(OPEN) 
 
See Protocol Section13.5 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
 
Participant Transfers: 
patienttransfer@crab.org 
 
Serious Adverse Event Reporting questions:  
See Protocol Section 8.6   
Email: adr@swog.org  
 
 


S2011 
 
 
Page 6 
Version Date 03/09/2023 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
For participant enrollments:
For 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 > 
Regulatory Submission.)  
 
Institutions with participants 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878)), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the participant enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN related questions by 
phone or email : 1-888-823-5923, 
or ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the 
data submission section of the 
protocol for further instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded from 
the protocol-specific page located on the CTSU members’ website (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 logging in with a CTEP-IAM 
username and password. or linked ID.me account (ID.me accounts are required for all newly created 
CTEP-IAM accounts and by July 1, 2023 for all users).  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).  Roster 
Maintenance application and in most cases viewable and manageable via the Roster Update 
Management System (RUMS) on the CTSU members’ website.
For participant eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center (SDMC) by phone or email: 
206/652-2267 
guquestion@crab.org 
 
For treatment or toxicity related questions contact the Study Chairs by phone or email: Dr. Sonpavde 
or Dr. Liss by phone or email. 
Dr. Sonpavde                                                                                  Dr. Liss 
Phone: 407/303-2024 (Mobile: 205-520-6512)                               Phone: 210/567-1100 
Email: guru.sonpavde.md@adventhealth.com                               Email:  liss@uthscsa.edu                         
 
For non-clinical questions (i.e. unrelated to participant eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 


S2011 
 
 
Page 7 
Version Date 03/09/2023 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration/Randomization
Arm A 
 
Gemcitabine + Carboplatin + 
Avelumab 
Arm B 
Surgery Only 
Radical Cystectomy or 
Nephroureterectomy or Ureterectomy 
(Within 6 weeks after randomization) 
Radical Cystectomy or 
Nephroureterectomy or 
Ureterectomy 
(4-8 weeks following last dose) 
Follow-Up for 
5 Years after Registration 


S2011 
 
 
Page 8 
Version Date 03/09/2023 
 
 
1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
a. 
To compare pathologic complete response (pCR, pT0N0) with avelumab plus 
gemcitabine and carboplatin (AGCa) vs. no neoadjuvant therapy preceding 
protocol surgery for muscle-invasive bladder cancer or upper tract urothelial 
carcinoma (MIBC/UTUC) for participants who are ineligible for cisplatin-based 
chemotherapy. 
 
1.2 
Secondary Objective(s) 
 
a. 
To evaluate toxicities with AGCa, and to compare resectability rates and surgical 
complications by arm in this population. 
 
b. 
To compare event-free survival (EFS) with AGCa versus no neoadjuvant therapy 
in this population.  
 
c. 
To compare overall survival (OS) with AGCa versus no neoadjuvant therapy 
preceding surgery in this population. 
 
d. 
To compare pathologic complete response (pCR, pT0N0) with avelumab plus 
gemcitabine and carboplatin (AGCa) vs. no neoadjuvant therapy preceding 
protocol surgery in the subset of participants who received at least 2 cycles of 
neoadjuvant therapy in Arm A. 
 
1.3 
Banking Objectives 
 
a. 
To bank tumor tissue, blood, and urine for future correlative genomic, 
transcriptomic, and proteomic studies to discover molecular signatures associated 
with pCR and resistance.  
 
 
2.0 
BACKGROUND 
 
2.1 
Neoadjuvant Therapy for Bladder Cancer: Knowledge Gap and Unmet Clinical Need in the 
Setting of Cisplatin-Ineligible Patients 
 
Level 1 data exist to support the use of neoadjuvant cisplatin-based combination 
chemotherapy preceding radical cystectomy (RC) for resectable (cT2-T4aN0M0) MIBC. (1, 
2, 3)  The SWOG-8710 Phase III trial demonstrated significantly improved outcomes with 
neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy 
compared to no neoadjuvant chemotherapy with a 5-year overall survival (OS) of 57% vs. 
43%.  The Medical Research Council trial also demonstrated improved OS (49% vs. 43% 
at 5 years) as well as disease-free survival (39% vs. 32% at 5 years) with neoadjuvant 
CMV (cisplatin, methotrexate, vinblastine). (2)   The depth of pathologic response has been 
shown to be associated with survival in the context of neoadjuvant cisplatin-based 
chemotherapy in the SWOG-8710 trial, with the best outcomes seen with pCR (pT0), which 
was observed in ~38% of patients receiving MVAC chemotherapy compared to ~15% of 
patients in the RC alone arm. (4)  However, data also suggest that the baseline age-
dependent increase in renal dysfunction rendering patient’s cisplatin-ineligible is common 
in MIBC and occurs in > 40% of patients > 70 year old. (5) Additionally, Zubrod-PS ≥ 2, 
neuropathy > Grade 1, hearing loss > Grade 1 and NYHA cardiac dysfunction > class 2 
have been accepted as criteria determining that patients are cisplatin-ineligible. (6) For 
such patients who are cisplatin-ineligible or refuse cisplatin chemotherapy, there is no 
established data to support use of neoadjuvant (or adjuvant) therapy. Gemcitabine plus 
carboplatin (GCa) is considered a community standard for those with metastatic disease 
for patients that cannot receive cisplatin. (7, 8, 9, 10, 11, 12, 13)  Small non-randomized 


S2011 
 
 
Page 9 
Version Date 03/09/2023 
 
 
and retrospective studies report the feasibility and modest benefit from delivering 
neoadjuvant GCa; the pCR rates have been 16-24%, with a suggestion of improved PFS. 
(14, 15, 16)   The uptake of neoadjuvant chemotherapy has been steadily increasing in the 
United States, and the application to cisplatin-ineligible patients will further increase its 
utility. (17)  Nevertheless, there is no established neoadjuvant regimen for cisplatin-
ineligible MIBC/UTUC. Thus, there is a significant knowledge gap and unmet need in the 
neoadjuvant therapy space for cisplatin-ineligible patients.  One recently reported Phase 
III trial (POUT) evaluated adjuvant platinum-based chemotherapy (cisplatin or carboplatin) 
for UTUC and identified a disease-free survival benefit leading to early stopping of the trial. 
(18)  Notably, in exploratory analyses, adjuvant GCa also appeared to be associated with 
benefit in the POUT trial, albeit to a lesser magnitude than gemcitabine plus cisplatin (GC), 
suggesting the hypothesis that GCa may confer benefits in the neoadjuvant setting for 
UTUC and MIBC also, albeit less than seen with GC. However, this trial only enrolled UTUC 
patients and did not evaluate neoadjuvant therapy, which appears more feasible to deliver. 
 
2.2 
Activity of Single Agent PD1/L1 Inhibitors in Urothelial Carcinoma 
 
Atezolizumab, avelumab and durvalumab, programmed death (PD)-ligand (L)-1 inhibitors, 
and the PD-1 inhibitors nivolumab and pembrolizumab are approved for patients relapsing 
after platinum-based first-line therapy.(19, 20, 21, 22, 23, 24)  All of these agents have 
similar activity with responses in ~20% of patients and manageable toxicities characterized 
by immune related adverse events. Atezolizumab and pembrolizumab are approved as 
first-line therapy for cisplatin-ineligible advanced UC with high PD-L1 expression or 
platinum-ineligible patients regardless of PD-L1 expression.(25)  More recently, avelumab 
extended survival regardless of tumor PD-L1 status as switch maintenance therapy in 
those with responding or stable disease on platinum-based first-line chemotherapy.(26)  
Multiple PD1 and PD-L1 inhibitors are undergoing evaluation in Phase III trials as adjuvant 
therapy following RC for high risk disease with or without prior neoadjuvant chemotherapy. 
Unfortunately, the IMvigor010 Phase III trial did not report improved outcomes with 
adjuvant atezolizumab for unselected patients with MIBC, although the results of other 
trials evaluating pembrolizumab and nivolumab are still pending. (27)    
 
Single agent pembrolizumab or atezolizumab appeared feasible with promising pathologic 
complete response rates (~30-40%) as neoadjuvant therapy followed by radical 
cystectomy for cisplatin-ineligible MIBC patients. (28, 29, 30, 31)  Intriguingly, the pCR rate 
with pembrolizumab appeared to be associated with high tumor PD-L1 protein expression 
by IHC, tumor mutation burden (TMB) and gene expression profile. (32, 33)  
Multiparametric magnetic resonance imaging (MRI) appeared promising as a radiomic 
modality to predict pathologic response in this trial. (34)  In the trial that evaluated 
neoadjuvant atezolizumab, preexisting activated T cells correlated with outcome. 
Responding tumors showed expression of genes related to tissue repair after treatment 
and stromal factors such as transforming growth factor (TGF)-β, fibroblast activation 
protein and cell cycle gene signatures were associated with resistance. 
 
2.3 
Activity of PD1/L1 Inhibitors in Combination with Platinum-Based Chemotherapy for 
Urothelial Carcinoma 
 
PD-1 and PD-L1 inhibitors are being combined with platinum-based combination 
chemotherapy and cytotoxic T-lymphocyte associated (CTLA)-4 inhibiting immune 
modulators in first-line metastatic disease randomized Phase III trials, which allow cisplatin-
ineligible patients regardless of PD-L1 expression.(24) Indeed, the IMvigor130 trial 
reported the improvement of progression-free survival with the combination of 
atezolizumab with platinum-based first-line chemotherapy for metastatic urothelial 
carcinoma regardless of tumor PD-L1 expression. (35, 36)  In contrast, the Phase III 
DANUBE first-line trial did not meet the primary endpoints of improving OS compared 
to gemcitabine-platinum for a chemotherapy-free checkpoint inhibitor alone strategy 
of durvalumab in patients with high tumor/immune cell PD-L1 or for durvalumab plus 
tremelimumab regardless of PD-L1 expression. (37)   


S2011 
 
 
Page 10 
Version Date 03/09/2023 
 
 
 
Recently reported Phase II trials evaluated neoadjuvant pembrolizumab or nivolumab in 
combination with cisplatin-based chemotherapy for cisplatin-eligible MIBC (NCT02736266, 
NCT023657)66). In the preliminary analysis, the authors note promising pathologic 
response activity for the combination of gemcitabine, cisplatin and pembrolizumab as 
neoadjuvant therapy for cisplatin-eligible patients with MIBC (the pCR rate was 44.4% and 
<pT2N0 rate was 61.1%). (38)  In contrast to the single agent pembrolizumab data, pCR 
was observed regardless of tumor PD-L1 protein expression with combination 
gemcitabine-cisplatin-pembrolizumab Similar data were also reported in a phase II trial 
recently for the combination of gemcitabine, cisplatin and nivolumab. (39)   Indeed, the 
combination of a PD1 inhibitor (pembrolizumab) with neoadjuvant chemotherapy 
significantly increased pCR rate in a phase III trial enrolling triple-negative breast cancer 
(which is biologically similar to urothelial carcinoma in many respects) regardless of tumor 
PD-L1 status. (40) Randomized phase III trials are planned to develop these chemo-
immunotherapy combinations as neoadjuvant therapy for cisplatin-eligible MIBC patients 
(NCT03661320, NCT03732677, NCT03924856). Randomized phase III trials are also 
planned in the neoadjuvant cisplatin-ineligible space using an immunotherapy alone 
strategy without a chemotherapy backbone (NCT03924895, 2018-002676-40). However, 
none of the planned industry-sponsored trials are capitalizing on the potential additive or 
synergistic efficacy regardless of PD-L1 expression when combining PD1/PD-L1 inhibitors 
with chemotherapy for cisplatin-ineligible MIBC.   
 
2.4 
Rationale to Support the Development of Neoadjuvant Avelumab in Combination with 
Gemcitabine and Carboplatin for Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma 
 
A significant unmet need exists in the context of cisplatin-ineligible patients with 
MIBC/UTUC. Currently, MIBC or high risk UTUC patients who are cisplatin-ineligible are 
offered upfront RC, nephroureterectomy or ureterectomy followed by trials in the adjuvant 
setting. Single agent PD1/L1 inhibitors show promising activity in the neoadjuvant setting, 
which may be confined to selected patients with high PD-L1 or high TMB tumors. (41, 42, 
43, 44)   Indeed, the failure of adjuvant atezolizumab as adjuvant therapy for unselected 
MIBC patients in the IMvigor010 trial is also consistent with the hypothesis that benefit from 
single agent perioperative PD1/L1 inhibitors may be confined to a selected subset of 
patients. Inferior outcomes have also been observed for single agent pembrolizumab or 
atezolizumab compared to platinum-based chemotherapy as first-line therapy for low PD-
L1 
expressing 
metastatic 
urothelial 
carcinoma 
patients 
(https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm612484.htm), 
which 
led to a change in the regulatory indication sanctioning its use in those with high tumor PD-
L1 expression. In contrast, there is a robust rationale to investigate PD1/PD-L1 inhibitors 
in combination with platinum-based chemotherapy as neoadjuvant therapy regardless of 
PD-L1 expression based on preliminarily promising data in the phase II neoadjuvant trials 
of cisplatin-eligible patients and the phase III IMvigor130 trial in the first-line metastatic 
disease setting. (45, 46, 47, 48)  The tumor in place affords the possibility of capitalizing 
on a large antigenic burden and converting a large number of PD1 expressing exhausted 
T cells in the tumor stroma to competent T cells that may traffic systemically and eliminate 
microscopic metastatic disease.  Furthermore, gemcitabine exhibits immune enhancing 
properties by clearing Tregs and MDSCs. (49, 50) The combination of PD1/L1 inhibitors 
with chemotherapy has also yielded benefits regardless of tumor PD-L1 expression in 
randomized trials of other malignancies with biologic similarities to urothelial carcinoma, 
e.g. triple negative breast cancer and small and non-small cell lung cancer. (51, 52, 53, 54)  
In contrast, single agent neoadjuvant PD1/L1 inhibitors may not yield robust benefits in 
unselected MIBC patients. Hence, given that GCa has yielded pathologic responses as 
neoadjuvant therapy and appears superior to PD1/L1 inhibitors in PD-L1 low patients as 
first-line therapy for metastatic urothelial carcinoma, it may represent a reasonable 
backbone to develop neoadjuvant therapy for cisplatin-ineligible MIBC in combination with 
a PD1/L1 inhibitor. Avelumab may also be expected to be feasible in combination with 
platinum-based chemotherapy, given similar efficacy and toxicity profiles for all PD1 and 
PD-L1 inhibitors; indeed, 1) the INDUCOMAIN phase II trial (NCT03390595) demonstrated 


S2011 
 
 
Page 11 
Version Date 03/09/2023 
 
 
the safety and activity of the combination of gemcitabine, carboplatin and avelumab (n=42) 
as first-line therapy for patients with metastatic urothelial carcinoma who were ineligible for 
cisplatin-based chemotherapy  and 2)  a phase III trial (Javelin Ovarian-100) has  
evaluating and reported safety of avelumab combined with carboplatin-based combination 
chemotherapy for ovarian cancer. This design allows the optimization of neoadjuvant 
therapy using the combination of GCa and avelumab, which may confer benefits to a broad 
cisplatin-ineligible MIBC population regardless of PD-L1 expression, when compared to 
the current convention of no neoadjuvant therapy and upfront radical surgery.  
 
This randomized phase II trial is comparing the current standard of upfront surgery without 
neoadjuvant therapy vs. the combination of carboplatin-based chemotherapy and PD-L1 
inhibition as neoadjuvant therapy of cisplatin-ineligible muscle-invasive bladder cancer 
(MIBC) and high risk UTUC patients. This is the first randomized trial employing a strategy 
of combining cytotoxic chemotherapy and an immune checkpoint inhibitor for cisplatin-
ineligible muscle-invasive bladder cancer and will provide transformative data in this space. 
Moreover, given that other industry-led randomized phase III trials evaluating checkpoint 
inhibitors in the neoadjuvant cisplatin-ineligible space are being planned without a 
chemotherapy backbone, this proposed trial will provide complementary evidence for a 
different strategy that leverages the known potentially additive or synergistic efficacy of 
GCa. This paradigm also offers the potential to interrogate tumor tissue and radiomics 
before and after therapy and identify a prognostic/predictive signature for benefit from the 
combination.(45, 46) While the level of pCR increment at the trial level that may translate 
to improved level long-term outcomes (PFS, OS) is unclear, a range of pCR improvement 
1-19% was associated with improved long-term outcomes in the setting of breast cancer. 
Hence, a strong rationale may be made to apply these guidelines to MIBC and an 
increment in pCR rate from 15% to 35% (i.e. similar to the SWOG8710 cisplatin-eligible 
trial) may be reasonably likely to translate to improved PFS and OS.(1-3) Notably, >80% 
of recurrence events occur within 2 years of RC, and a robust association of PFS at 2 years 
with OS at 5 years at the individual patient level has been established. (55, 56, 57) 
Correlative studies (tumor tissue genomics, transcriptomics and proteomics) may be 
utilized to develop precision medicine and understand tumor biology and resistance 
mechanisms. Noninvasive correlative studies including peripheral blood immune studies, 
circulating tumor (ct)-DNA profiling and radiomics alterations may complement efforts to 
develop precision medicine by correlating with pathologic outcomes. (58, 59, 60, 61)   
 
2.5 
Inclusion of Women and Minorities and Planned Enrollment Report 
 
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 
1 
0 
0 
1 
Asian 
1
2
0
0 
3
Native Hawaiian 
or Other Pacific 
Islander
0 
1 
0 
0 
1 
Black or African 
American 
2 
7 
0 
0 
9 
White 
26
147
2
7 
182
More Than One 
Race 
0 
0 
0 
0 
0 


S2011 
 
 
Page 12 
Version Date 03/09/2023 
 
 
Total 
29
158
2
7 
196
 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures  
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, gemcitabine and carboplatin are commercially available; therefore, Investigator 
Brochures are not applicable to these drugs.  Information about commercial drugs is publicly 
available in the prescribing information and other resources. 
 
For this study, avelumab is investigational and is being provided under an IND held by SWOG.  For 
INDs filed by SWOG, the protocol serves as the Investigator Brochure for the performance of the 
protocol.  In such instances, submission of the protocol to the IRB should suffice for providing the 
IRB with information about the drug.  However, in cases where the IRB insists on having the official 
Investigator’s Brochure from the company, further information may be requested by contacting the 
SWOG Operations Office at 210/614-8808. 
 
3.1 
Avelumab (MSB0010718C; Bavencio) (NSC-799232, IND-156359)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Avelumab binds PD-L1 and blocks the interaction between 
PD-L1 and PD-1. This removes the suppressive effects of PD-L1 on antitumor 
CD8+ T cells, resulting in the restoration of cytotoxic T cell response.  
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Avelumab is administered intravenously and is 100% 
bioavailable. 
 
2. 
Distribution: Avelumab is expected to be distributed in the systemic 
circulation and to a lesser extent into the extracellular space. In vitro 
studies suggest that avelumab binds to human tissues that are known for 
PD-L1 expression: various epithelial cell types, endothelium, mononuclear 
cells 
(including 
dendritic 
cells, 
lymphocytes, 
monocytes 
and 
macrophages), pancreatic islets, placental trophoblasts and decidual 
cells, smooth muscle cells, and mesenchymal stem cells.  The volume of 
central and peripheral compartments are estimated to be 2.84L and 1.21L 
in the typical subject, respectively. The geometric mean Vss for a subject 
receiving 10mg/kg was 4.72L, which is consistent with distribution mainly 
limited to systemic circulation. 
 
3. 
Metabolism: Avelumab is degraded by proteolytic catabolism. CYP450 
does not contribute to its metabolism. 
 
4. 
Elimination: The primary route of elimination of avelumab is through 
proteolytic degradation. The geometric mean clearance calculated by 
noncompartmental analyses [Study EMR100070-001] was estimated as 
0.362mL/hr/kg for an initial 10mg/kg/dose. The corresponding value for 
Japanese subjects [Study EMR100070-002] was calculated as 
0.471mL/hr/kg at the 10mg/kg dose. The estimate of clearance obtained 
for a typical subject in population pharmacokinetic analysis was 0.0246 
L/hr. Population pharmacokinetic analysis and noncompartmental 
analysis results are comparable.  Based on exposure efficacy and 
exposure safety relationships, there are no expected clinically meaningful 


S2011 
 
 
Page 13 
Version Date 03/09/2023 
 
 
differences in the safety or efficacy of avelumab administered every 2 
weeks at 800 mg or 10 mg/kg in patients with metastatic Merkel cell 
carcinoma, urothelial carcinoma, and advanced renal cell carcinoma.  
 
c. 
ADVERSE EFFECTS  
 
1. 
Adverse Effects:  
 
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/
aeguidelines.pdf for further clarification. Frequency is provided based on 
1738 patients. Below is the CAEPR for Avelumab. 
 
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 2.0, April 23, 20191 
 
 Adverse Events with Possible Relationship to Avelumab 
 (CTCAE 5.0 Term) 
[n= 1738] 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia
CARDIAC DISORDERS
 
Myocarditis2 
 
Pericarditis2 
ENDOCRINE DISORDERS
 
Adrenal insufficiency2
 
Hyperthyroidism2
 
Hypophysitis2 
 
Hypopituitarism2 
 
Hypothyroidism2
EYE DISORDERS
 
Uveitis2 
GASTROINTESTINAL DISORDERS
 
Abdominal pain
 
Colitis2 
 
Diarrhea
 
Nausea
 
Pancreatitis2
 
Vomiting
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS


S2011 
 
 
Page 14 
Version Date 03/09/2023 
 
 
 
 Adverse Events with Possible Relationship to Avelumab 
 (CTCAE 5.0 Term) 
[n= 1738] 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
 
Chills
Fatigue
 
Fever
 
Flu like symptoms3
HEPATOBILIARY DISORDERS
 
Hepatic failure2 
 
Hepatobiliary disorders -
Other 
(autoimmune 
hepatitis, 
immune-related 
hepatitis)2 
IMMUNE SYSTEM DISORDERS
 
Autoimmune disorder2
 
Cytokine 
release 
syndrome3 
 
Immune system disorders -
Other (sarcoidosis)2 
INFECTION AND INFESTATIONS
 
Infection4
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
 
Infusion related reaction3
INVESTIGATIONS
 
Alanine aminotransferase 
increased
 
Alkaline 
phosphatase 
increased 
 
Aspartate 
aminotransferase 
increased 
 
Blood bilirubin increased
 
CPK increased
 
Creatinine increased
 
GGT increased
 
Lipase increased
 
Lymphocyte 
count 
decreased
 
Neutrophil 
count 
decreased 
 
Platelet count decreased
 
Serum amylase increased
 
Thyroid 
stimulating 
hormone increased
METABOLISM AND NUTRITION DISORDERS
 
Anorexia
 
Hyperglycemia2 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
 
Arthralgia2


S2011 
 
 
Page 15 
Version Date 03/09/2023 
 
 
 
 Adverse Events with Possible Relationship to Avelumab 
 (CTCAE 5.0 Term) 
[n= 1738] 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
 
Generalized 
muscle 
weakness 
 
Muscle cramp
 
Myalgia2
 
Myositis2 
 
Pain in extremity
NERVOUS SYSTEM DISORDERS
 
Encephalopathy2
 
Guillian-Barre syndrome2
 
Myasthenia gravis2
 
Nervous system disorders -
Other 
(non-infectious 
encephalitis)2 
 
Nervous system disorders -
Other 
(non-infectious 
meningitis)2 
 
Peripheral 
motor 
neuropathy 
 
Peripheral 
sensory 
neuropathy2 
RENAL AND URINARY DISORDERS
 
Renal and urinary disorders 
- Other (immune related 
nephritis)2 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
 
Cough
 
Pneumonitis2 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Eczema
 
Pruritus
 
Rash acneiform
 
Rash maculo-papular
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, the name of the investigator, 
the protocol and the agent should be included in the e-mail.  
2 Immune-mediated adverse reactions have been reported in patients 
receiving avelumab. Adverse events potentially related to avelumab 
may be manifestations of immune-mediated adverse events. In clinical 
trials, most immune-mediated adverse reactions were reversible and 
managed 
with 
interruptions 
of 
avelumab), 
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 avelumab, may manifest as fever, 
chills, shakes, itching, rash, hypertension or hypotension, or difficulty 
breathing during and immediately after administration of avelumab.  


S2011 
 
 
Page 16 
Version Date 03/09/2023 
 
 
4 Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC.  
 
Adverse events reported on avelumab trials, but for which there is 
insufficient evidence to suggest that there was a reasonable 
possibility that avelumab caused the adverse event:  
 
CARDIAC DISORDERS - Palpitations; Sinus tachycardia  
EYE DISORDERS - Blurred vision; Dry eye  
GASTROINTESTINAL 
DISORDERS 
- 
Abdominal 
distension; 
Constipation; Dry mouth; Dyspepsia; Flatulence; Mucositis oral  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Edema limbs; Localized edema; Malaise; Non-cardiac chest pain; Pain  
INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; 
Investigations - Other (c-reactive protein increased); Weight gain; Weight 
loss  
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Back pain; Bone pain  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (tumor flare); Tumor pain  
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysgeusia; 
Headache; Tremor  
RENAL AND URINARY DISORDERS - Proteinuria  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Dyspnea; Hypoxia  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis  
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension 
 
Note:  Avelumab 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. 
 
2. 
Pregnancy and Lactation: Based on its mechanism of action, avelumab 
can cause fetal harm when administered to a pregnant woman. Advise 
females of reproductive potential to use effective contraception during 
treatment with avelumab and for at least one month after the last dose of 
avelumab. There is no information regarding the presence of avelumab in 
human milk, the effects on the breastfed infant or the effects on milk 
production. Since many drugs including antibodies are excreted in human 
milk, advise lactating women not to breastfeed during treatment and for at 
least one month after the last dose of avelumab due to the potential for 
serious adverse reactions in breastfed infants.  
 
3. 
Special Populations: No dedicated clinical studies have been conducted 
to evaluate the effect of renal or hepatic impairment on the 
pharmacokinetics of avelumab. Even though a limited number of patients 
with severe renal impairment have been studied renal impairment is not 
expected to have an effect on the pharmacokinetics of avelumab. There 
are limited data from patients with severe hepatic impairment, and the 
effect of severe hepatic impairment on the pharmacokinetics of avelumab 
is not known.  
 
 


S2011 
 
 
Page 17 
Version Date 03/09/2023 
 
 
 
4. 
Drug Interactions: No interaction studies have been conducted with 
avelumab in humans.  
 
Note: Avelumab 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. 
 
d. 
DOSING & ADMINISTRATION  
 
See Section 7.0 Treatment Plan.  
 
e. 
HOW SUPPLIED  
 
Avelumab is supplied by Merck KGaA/EMD Serono, Inc. and distributed by  
McKesson as single-use 200 mg vials containing a sterile solution of 10 mL total 
volume (20 mg/ml). Avelumab is a clear and colorless to slightly yellow concentrate 
for solution containing D-mannitol, glacial acetic acid, polysorbate 20, sodium 
hydroxide, and water for injection, and supplied in glass vials closed with a rubber 
(not made with natural rubber latex) stopper and sealed with an aluminum crimp 
seal closure fitted with a removable plastic cap.  
 
f. 
STORAGE, PREPARATION & STABILITY  
 
1. 
Avelumab must be stored under refrigeration (2°-8° C, 36-46º F) and 
protected from light until use. Avelumab must not be frozen. Rough 
shaking must be avoided during handling and preparation.  
 
2. 
Avelumab must be diluted in 0.9% sodium chloride solution. Avelumab 
may also be diluted in 0.45% sodium chloride solution, if necessary. 
Prepared solutions of avelumab should be used immediately. If not used 
immediately, diluted avelumab may be stored for up to 4 hours at room 
temperature (15°C-25°C) or up to 24 hours under refrigeration (2°C to 
8°C); this includes infusion time.  
 
g. 
DRUG ORDERING AND ACCOUNTABILITY 
 
1. 
Drug ordering: Drug orders must be submitted by faxing the Drug Order 
Form – SWOG S2011 to McKesson at the number listed on the order form. 
This form can be found on the SWOG website (www.swog.org) or on the 
CTSU website (www.ctsu.org). 
 
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 or disposal of all drugs 
received from the supplier using the NCI Drug Accountability Record Form 
(DARF) available at http://ctep.cancer.gov.Electronic logs are allowed as 
long as a print version of the log process is the exact same appearance 
as the current NCI DARF.  
 
3. 
Drug Returns: Unused or expired drug supplies MUST be returned to 
McKesson for disposal. Any partially opened vials need to be destroyed 
on site per institutional policy. 
 
4. 
Questions about drug orders, transfers, returns, or accountability should 
be addressed to protocols@swog.org.  
 
3.2 
Gemcitabine hydrochloride (Gemzar®) (NSC-613327) 


S2011 
 
 
Page 18 
Version Date 03/09/2023 
 
 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action:  
Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and 
triphosphate 
(dFdCTP) 
nucleosides. 
Gemcitabine 
diphosphate 
inhibits 
ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that 
generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions 
in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate 
competes with dCTP for incorporation into DNA. The reduction in the intracellular 
concentration of dCTP by the action of the diphosphate enhances the incorporation 
of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine 
nucleotide is incorporated into DNA, only one additional nucleotide is added to the 
growing DNA strands, which eventually results in the initiation of apoptotic cell 
death. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption and Distribution: Gemcitabine pharmacokinetics are linear and 
are described by a 2-compartment model. Population pharmacokinetic 
analyses of combined single and multiple dose studies showed that the 
volume of distribution of gemcitabine was significantly influenced by 
duration of infusion and gender. Gemcitabine plasma protein binding is 
negligible. The volume of distribution is increased with the infusion 
duration. In a pharmacokinetics study of patients with various solid tumors, 
the volume of distribution of gemcitabine was 50 L/m2 following infusions 
lasting <70 minutes. For long infusions (70 to 285 minutes), the volume of 
distribution rose to 370 L/ m2.   
 
2. 
Metabolism: Gemcitabine is metabolized intracellularly to form active 
gemcitabine di- and tri-phosphates.  The gemcitabine di- and tri-
phosphates do not appear to circulate in plasma in measurable amounts.  
Gemcitabine is metabolized by the liver to form the inactive uracil 
derivative, 2'-deoxy-2',2'-difluorouridine (dFdU).  The inactive metabolite 
does not appear to accumulate with weekly dosing; however, it is excreted 
by the kidneys and may accumulate in patients with decreased renal 
function. 
 
3. 
Elimination: Following a single 1,000 mg/m2/30 min [14C]-gemcitabine 
infusion, 92% to 98% of the dose was recovered within 1 week after 
gemcitabine administration.  Urinary excretion of the parent drug and the 
dFdU metabolite accounted for 99% of the excreted dose, and less than 
1% of the dose was excreted in feces.  The renal clearance of gemcitabine 
is less than 10%; therefore, the parent drug appears to be almost 
completely metabolized to the inactive dFdU. 
 
Clearance of gemcitabine is affected by age and gender and is lower in 
women and the elderly.  Differences in either clearance or volume of 
distribution based on patient characteristics or the duration of infusion 
result in changes in half-life and plasma concentrations. Studies showed 
that gemcitabine half-life for short infusions ranged from 42 to 94 minutes, 
for long infusions it varied from 245 to 638 minutes, depending on age and 
gender, reflecting a greatly increased volume of distribution with longer 
infusions. The terminal phase half-life for the active metabolite, 
gemcitabine triphosphate, in mononuclear cells ranges from 1.7-19.4 
hours. 
 
c. 
ADVERSE EFFECTS  


S2011 
 
 
Page 19 
Version Date 03/09/2023 
 
 
 
1. 
Possible Side Effects of gemcitabine:  
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in >20% to 100% of subjects treated with 
gemcitabine include: flu-like symptoms, nausea, vomiting, rash, alopecia, 
infection, myelosuppression including anemia, leukopenia, neutropenia, 
and thrombocytopenia, muscle weakness, hematuria, paresthesia, 
sensory neuropathy, fatigue, somnolence, peripheral edema. 
 
Adverse effects reported in 4% to 20% of subjects include: diarrhea, 
constipation, stomatitis, dyspnea, capillary leak syndrome, posterior 
reversible encephalopathy syndrome (PRES), extravasation.  
 
Adverse effects reported in 3% or less of subjects include: arrhythmias, 
supraventricular arrhythmias, congestive heart failure, myocardial 
infarction, desquamation and bullous skin eruptions, gangrene, 
cerebrovascular accident, hepatic failure, adult respiratory distress 
syndrome (ARDS), anaphylaxis, renal failure, pulmonary fibrosis, 
pulmonary 
edema, 
and 
Interstitial 
pneumonitis, 
hemorrhage, 
hypertension, sepsis.  
 
2. 
Pregnancy and Lactation: Category D. Gemcitabine may cause fetal harm 
when administered to a pregnant woman.  This agent has produced 
teratogenic effects in mice and rabbits when administered at a dose of < 
2 mg/m2.  Adverse effects included decreased fetal viability, weight and 
morphologic defects.  There is no data on gemcitabine administration 
during human pregnancy, and it is not currently known if metabolites are 
excreted in human milk.  However, many drugs are excreted in human 
milk, and there is a potential for adverse effects in nursing infants.  
Therefore, the use of gemcitabine should be avoided in pregnant or 
nursing women because of the potential hazard to the fetus or infant. 
 
3. 
Drug Interactions: Per gemcitabine package insert, no formal drug 
interaction studies have been performed to date.  When gemcitabine was 
administered with carboplatin or paclitaxel there was minimal or no effect 
on the pharmacokinetics of the studied drugs. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan  
 
e. 
HOW SUPPLIED  
 
Gemcitabine is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
 


S2011 
 
 
Page 20 
Version Date 03/09/2023 
 
 
 
3.3 
Carboplatin (CBDCA) (NSC-241240)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Carboplatin (CBDCA) is a hydrophilic platinum coordination 
compound and is an analog of cisplatin, producing intrastrand DNA cross-links. 
 
b. 
PHARMACOKINETICS 
 
1. 
Distribution: Vd = 16 L 
 
2. 
Protein Binding: Carboplatin is not bound to plasma proteins.  
 
3. 
Elimination: The initial half-life is 1.1 - 2.0 hours and the post-distributional 
half-life is 2.6 - 5.9 hours. Sixty-five percent of the dose is excreted in the 
urine within twelve hours.   
 
c. 
ADVERSE EFFECTS 
 
1. 
Possible Side Effects of Carboplatin: 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
2. 
Pregnancy and Lactation: Pregnancy Category D. Carboplatin may cause 
fetal harm, therefore women of childbearing potential should be advised 
to avoid becoming pregnant. 
 
3. 
Drug Interactions: Due to potential drug interactions, a complete patient 
medication list, including Carboplatin, should be screened prior to initiation 
of and during treatment with Carboplatin. See Section 8.0 Toxicities to be 
Monitored and Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
Carboplatin is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
 
4.0 
STAGING CRITERIA 
 
4.1 
Staging Criteria (AJCC, Eighth Edition)   
 
Bladder 
T2 
Tumor invades the muscularis propria 
T3  
For renal pelvis only: Tumor invades beyond muscularis into peripelvic fat or into 
the renal parenchyma  
For ureter only: Tumor invades beyond muscularis into periureteric fat 
T4a 
Extravesical tumor directly invades any of the following: Prostatic stroma, seminal 
vesicles, uterus, vagina 
 
 
T4b 
Extravesical tumor invades pelvic wall or abdominal wall 
 
NX  
Regional lymph nodes cannot be assessed 


S2011 
 
 
Page 21 
Version Date 03/09/2023 
 
 
N0  
No regional lymph node metastasis 
 
M0  
No distant metastasis 
 
Upper tract 
T2 
Tumor invades the muscularis 
T3  
For renal pelvis only: Tumor invades beyond muscularis into peripelvic fat or into 
the renal parenchyma.  For ureter only: Tumor invades beyond muscularis into 
periureteric fat 
T4  
Tumor invades adjacent organs, or through the kidney into the perinephric fat 
 
NX  
Regional lymph nodes cannot be assessed 
N0  
No regional lymph node metastasis 
 
M0  
No distant metastasis 
 
4.2 
Method of staging 
 
Contrast-enhanced computed tomography of the chest, abdomen, and pelvis should be 
performed for tumor stage assessments whenever possible. Images should be acquired 
with slice thickness of 5 mm or less. Tumor measurements should be made by the same 
investigator or radiologist for each assessment whenever possible.  
 
If a participant has a contraindication for CT IV contrast, a non-contrast CT of the chest 
and a gadolinium contrast-enhanced MRI of the abdomen and pelvis may be obtained. 
 
If a contraindication for both MRI and CT intravenous contrasts exists, a non-contrast CT 
of the chest and a non-contrast MRI of the abdomen and pelvis should be obtained. 
 
If a participant has contraindication for MRI (e.g., pacemaker) in addition to contraindication 
to CT intravenous contrast, a non-contrast CT of the chest, abdomen and pelvis is 
acceptable. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a participant to be considered eligible 
for registration in OPEN.  Section 5 may be printed and used to by the site, but is not to be uploaded in 
RAVE (unless specially stated).  For each criterion requiring test results and dates, please record this 
information on the Onstudy Form and submit via Medidata Rave® (see Section 14.3).  Any potential 
eligibility issues should be addressed to the SWOG SDMC in Seattle at 206/652-2267 or 
guquestion@crab.org prior to registration. NCI policy does not allow for waiver of any eligibility 
criterion (http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm).  
 
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 4 weeks later would be considered Day 28.  This 
allows for efficient participant scheduling without exceeding the guidelines.   
 
5.1 
Disease Related Criteria 
 
a. 
Participants must have one of the following: 
 
 
A histologically documented muscle-invasive bladder carcinoma (MIBC) 
from TURBT within 120 days prior to registration.   
 
 


S2011 
 
 
Page 22 
Version Date 03/09/2023 
 
 
o 
All participants must have a TURBT (or re-TURBT) within 70 
days prior to registration and are eligible even if there is no 
muscle-invasion present in the re-TURBT. 
 
 
A histologically confirmed high grade upper tract urothelial carcinoma 
(UTUC) within 120 days prior to registration, with invasion confirmed by 
either a mass on cross-sectional imaging or a tumor directly visualized 
during upper urinary tract endoscopy within 120 days prior to registration.  
o 
All participants require a ureteroscopy with biopsy if feasible (or 
re-biopsy) within 70 days prior to registration and are eligible even 
if there is no muscle-invasion present in the re-biopsy. 
 
Participants diagnosed with mixed urothelial carcinoma and variant histology 
within 120 days prior to registration may be eligible if the majority (>50%) of the 
tumor consists of urothelial carcinoma.  Participants with pure non-urothelial 
variant histologies or any small cell histology are not eligible.   
 
b. 
Participants must have clinical stage T2-T4aN0M0 bladder or upper tract cancer 
confirmed by radiologic staging (CT scan/MRI abdomen and pelvis, and CT 
scan/x-ray of the chest) within 56 days prior to registration.  
 
c. 
Participants must have a bone scan within 56 days prior to registration if they have 
bone pain or elevated serum alkaline phosphatase. 
 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Participants must not have received prior systemic chemotherapy, immunotherapy 
or radiotherapy for the treatment of muscle invasive bladder cancer (MIBC) or 
upper tract urothelial carcinoma (UTUC).  Other prior pelvic radiotherapy is allowed 
if it does not preclude surgery (radical cystectomy, nephroureterectomy or 
ureterectomy, based on location of primary tumor).  Prior intravesical therapy is 
allowed. 
 
b. 
Participants must not have received immunosuppressive medication within 14 
days prior to registration, with the exception of intranasal, inhaled, topical steroids, 
or local steroid injections (e.g., intra-articular injection) systemic corticosteroids at 
physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Participants must be ≥ 18 years of age. 
 
b. 
Participants must have Zubrod Performance Status 0-2 (see Section 10.4). 
 
c. 
Participants must have history and physical examination within 28 days prior to 
registration.   
 
d. 
Participants must be surgical candidates as deemed by the local site oncologic 
surgeon within 28 days prior to registration.  This must be clearly documented. 
 
e. 
Participants must have a serum creatinine ≤ the IULN OR measured OR calculated 
creatinine clearance ≥ 30 mL/min using the Cockroft-Gault Formula below. This 
specimen must have been drawn and processed within 28 days prior to 
registration: 
 


S2011 
 
 
Page 23 
Version Date 03/09/2023 
 
 
Calculated Creatinine Clearance = (140 - age) X (weight in kg)† 
 
 72 x serum creatinine* 
 
Multiply this number by 0.85 if the participant is a female.  
 
† The kilogram weight is the participant weight with an upper limit of 140% of the IBW. 
* Actual lab serum creatinine value with a minimum of 0.7 mg/dL. 
 
f. 
Participants must be deemed cisplatin-ineligible based on greater than or equal to 
1 of the following:  
 
 
Zubrod performance status=2 
 
creatinine clearance (calculated by Cockroft-Gault formula or measured) 
30 to <60 ml/min,  
 
neuropathy >grade 1 
 
hearing loss >grade 1 
 
congestive heart failure >grade 2. 
 
g. 
Participants must have adequate organ and marrow function as defined below 
within 28 days prior to registration: 
 
hemoglobin  
 
 
 
 
≥ 9.0 g/dL 
 
absolute neutrophil count 
 
≥ 1,500/mcL 
 
platelets 
 
 
 
 
 
≥ 100,000/mcL 
 
total bilirubin 
 
 
 
≤ 1.5 x institutional upper limit of normal 
(ULN) , (≤ 3 x ULN if Gilbert’s disease) 
 
AST 
 
 
 
 
 
 
≤ 2.5 × institutional ULN 
 
ALT 
 
 
 
 
 
      ≤ 2.5 × institutional ULN 
 
h. 
Participants with known history or current symptoms of cardiac disease, or history 
of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification (see 
Appendix 18.1) and be class 2B or better. 
 
i. 
Participant must not have any other prior malignancy except for the following:  
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, 
prostate cancer Gleason score ≤ 3+4 in active surveillance, adequately treated 
Stage I or II cancer from which the participant is currently in complete remission, 
or any other cancer from which the participant has been disease free for two years. 
 
j. 
Participants must not be pregnant or nursing due to the risk of harm to a fetus or 
nursing infant. Women/men of reproductive potential must have a negative serum 
or urine pregnancy test within 28 days prior to registration and must have agreed 
to use an effective contraceptive method.  A woman is considered to be of 
"reproductive potential" if she has had menses at any time in the preceding 12 
consecutive months.  In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.  However, if at any 
point a previously celibate participant chooses to become heterosexually active 
during the time period for use of contraceptive measures outlined in the protocol, 
he/she is responsible for beginning contraceptive measures. 
 
k. 
Participants with known human immunodeficiency virus (HIV) must be on effective 
anti-retroviral therapy and have undetectable viral load at their most recent viral 
load test and within 6 months prior to registration. 
 
l. 
Participants must not have a history of active primary immunodeficiency. 
 


S2011 
 
 
Page 24 
Version Date 03/09/2023 
 
 
m. 
Participants must not have a history of or active autoimmune or inflammatory 
disorder, with the exception of vitiligo, alopecia, hypothyroidism (stable on 
hormone replacement), or chronic skin condition that does not require systemic 
therapy. 
 
 


S2011 
 
 
Page 25 
Version Date 03/09/2023 
 
 
 
5.4 
Specimen Submission Criteria 
 
a. 
Participants must be offered the opportunity to participate in specimen banking as 
outlined in Section 15.1.  
 
5.5 
Regulatory Criteria 
 
a. 
Participants must be informed of the investigational nature of this study and must 
sign and give informed consent in accordance with institutional and federal 
guidelines. 
 
NOTE:  As a part of the OPEN registration process (see Section 13.2 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 
 
Participants will be randomized 1:1 using a dynamic balancing algorithm with stratification based 
on the following factors: 
 
a. 
Clinical stage (cT2N0M0 vs cT3-4aN0M0) 
 
b. 
Zubrod performance status (0-1 vs 2)  
 
c. 
Calculated or measured creatinine clearance 30 to < 60 vs ≥ 60 ml/min 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Sonpavde at 617/632-2429.  For 
surgery related questions, please contact Dr. Liss at 210/567-1100.  For dosing principles or 
questions, please consult the SWOG Policy #38 "Dosing Principles for Participants on Clinical 
Trials" at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf. 
 
It is recommended that participants have a bimanual examination under anesthesia within 120 days 
prior to registration for both Arms A and B. 
 
 
7.1 
Treatment 
 
a. 
Arm A:  Gemcitabine + Carboplatin + Avelumab + Surgery 
 
Initiation of treatment for Arm A must be planned to start no more than 14 calendar 
days after registration.  Surgery must be planned within 4-8 weeks of last dose of 
neoadjuvant treatment.  
  
 
Agent 
Dose 
Route 
Day 
Schedule*  
 
 
Gemcitabine 
1000 mg/m2 
IV over 30m 1, 8 
Every 3 weeks x 4  
 
Carboplatin 
AUC 4.5** 
IV over 30m 1 
Every 3 weeks x 4  
 
Avelumab 
800 mg  
IV over 60m 1 
Every 2 weeks x 6  


S2011 
 
 
Page 26 
Version Date 03/09/2023 
 
 
 
 
 
 
 
 
 
 
* 1 Cycle = 21 days. See Table 7.1a below for an outline of how study treatment 
falls across days within each cycle and within the overall weeks of study treatment. 
See also section 9.1. 
** Note:  Escalate to AUC 5 from Cycle 2 forward if no dose limiting toxicities 
 
Table 7.1a:  Study Treatment Timing 
 
Cycle 1
Cycle 2
Cycle 3 
Cycle 4
Day of Cycle 
D 
1 
D 
8
D 
15
D 
1
D 
8
D 
15
D 
1
D 
8 
D 
15 
D 
1 
D 
8
D 
15
Gemcitabine 
X
X
X
X
X
X 
 
X 
X
Carboplatin 
X
X
X
 
 
X 
Avelumab 
X
X
X
X
 
X 
 
X
Week of 
Overall 
Treatment 
W 
1 
W 
2 
W 
3 
W 
4 
W 
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10 
W 
11
W
12
 
 
 
Gemcitabine should be given first, then carboplatin, then avelumab (to be given in 
order listed in table above). 
 
Avelumab is given after pre-medications acetaminophen 650 mg PO plus 
diphenhydramine 25-50 mg IV/PO.  Monitor participants for signs and symptoms 
of infusion-related reactions including pyrexia, chills, flushing, hypotension, 
dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the 
rate of infusion for mild or moderate infusion-related reactions. Stop the infusion 
and permanently discontinue avelumab for severe (Grade 3) or life-threatening 
(Grade 4) infusion-related reactions.  
 
If avelumab has to be held for toxicities, gemcitabine and carboplatin may continue 
with dose modifications if necessary, for gemcitabine/carboplatin related toxicities. 
If 
gemcitabine 
and/or 
carboplatin 
are 
held 
for 
toxicities 
related 
to 
gemcitabine/carboplatin, avelumab may continue if no prohibitive toxicities related 
to avelumab are observed. 
 
SURGERY 
 
Radical Cystectomy, Nephroureterectomy or Ureterectomy 
 
Radical cystectomy will be scheduled per surgeon’s discretion as standard of care 
procedure, within 4-8 weeks after final neoadjuvant therapy in Arm A.  Surgical 
approach (open, laparoscopic, or robotic assistance) is at surgeon’s discretion.  At 
minimum, a standard lymph node dissection must be performed at the time of the 
radical cystectomy. All potential node bearing tissue should be removed within the 
following boundaries: laterally the genitofemoral nerve; distally Cooper’s ligament 
to include the lymph node of Cloquet; proximally the common iliac bifurcation; 
medially the bladder to include the tissue medial to the hypogastric artery; and 
posteriorly the floor of the obturator fossa with circumferential mobilization of the 
external iliac artery and vein unless contraindicated due to extensive 
atherosclerotic vascular disease.  
 
In participants proceeding to nephroureterectomy or ureterectomy for upper tract 
urothelial carcinoma, regional template lymph node dissection is performed per 


S2011 
 
 
Page 27 
Version Date 03/09/2023 
 
 
surgeon discretion within 4-8 weeks after final neoadjuvant therapy. Urinary 
bladder cuff is routinely excised, and regional lymph node dissection is performed 
according to tumor location, including hilar, paracaval, retrocaval, and inter-
aortocaval nodes for right renal pelvic, proximal, and/or mid ureteral tumors; hilar 
and para-aortic nodes for left renal pelvic, proximal, and/or mid ureteral tumors; 
and ipsilateral common iliac, external iliac, internal iliac, and obturator nodes for 
distal ureteral tumors. Given little prospective data on the utility of routine lymph 
node dissection in UTUC, template-based lymphadenectomy is encouraged, but 
is not mandated. 
 
b. 
Arm B:  Surgery Only 
 
Surgery should be performed within 6 weeks after registration. 
 
Surgery (Radical Cystectomy, Nephroureterectomy or Ureterectomy) 
 
Radical cystectomy will be scheduled per surgeon’s discretion as standard of care 
procedure, within 6 weeks from registration in Arm B. Surgical approach (open, 
laparoscopic, or robotic assistance) is at surgeon’s discretion. At minimum, a 
standard lymph node dissection must be performed at the time of the radical 
cystectomy. All potential node bearing tissue should be removed within the 
following boundaries: laterally the genitofemoral nerve; distally Cooper’s ligament 
to include the lymph node of Cloquet; proximally the common iliac bifurcation; 
medially the bladder to include the tissue medial to the hypogastric artery; and 
posteriorly the floor of the obturator fossa with circumferential mobilization of the 
external iliac artery and vein unless contraindicated due to extensive 
atherosclerotic vascular disease.  
 
In participants proceeding to nephroureterectomy or ureterectomy for upper tract 
urothelial carcinoma, regional template lymph node dissection is performed per 
surgeon discretion, within 6 weeks after registration. Urinary bladder cuff is 
routinely excised, and regional lymph node dissection is performed according to 
tumor location, including hilar, paracaval, retrocaval, and inter-aortocaval nodes 
for right renal pelvic, proximal, and/or mid ureteral tumors; hilar and para-aortic 
nodes for left renal pelvic, proximal, and/or mid ureteral tumors; and ipsilateral 
common iliac, external iliac, internal iliac, and obturator nodes for distal ureteral 
tumors. Given little prospective data on the utility of routine lymph node dissection 
in UTUC, template-based lymphadenectomy is encouraged, but is not mandated. 
 
7.2 
Disease/Recurrence Assessment 
 
Participants’ disease will be followed for 5 years after registration.  
 
See Section 9.0 for disease assessment time points  
 
ARM A: Disease assessment at the end of neoadjuvant systemic therapy, but prior to 
surgery (CT/MRI abdomen and pelvis, and x-ray/CT of the chest). 
 
ARMS A and B: CT/MRI abdomen and pelvis, and x-ray/CT of the chest approximately 
every 12 weeks following surgery for 2 years, followed by CT/MRI abdomen and pelvis, 
and x-ray/CT chest annually in years 3-5. Disease assessment timing is to be based on 
calendar timing counted as weeks after registration, not based on cycles or drug 
administration. 
 
7.3 
DMU Demography monitoring and enrolling patients via OPEN 
 
Required submission of patient demographic data for this study will be submitted 
automatically via OPEN.   


S2011 
 
 
Page 28 
Version Date 03/09/2023 
 
 
 
Note: Serious adverse events must be submitted via CTEP-AERS per protocol guidelines. 
 
7.4 
Criteria for Removal from Protocol Treatment 
 
a. 
Neoadjuvant Therapy 
 
1. 
Progression/recurrence of disease or symptomatic deterioration per 
participant or physician judgment (as defined in Section 10.1). 
 
2. 
Unacceptable toxicity.  
 
3. 
Systemic treatment delay for any reason > 21 calendar days.  
 
4. 
The participants may withdraw from the protocol treatment at any time for 
any reason. 
 
5. 
Starting non-protocol anti-cancer therapy. 
 
b. 
Surgery 
 
1. 
Refusal of surgery. 
 
2. 
Delay of surgery greater than 8 weeks after last neoadjuvant treatment 
(Arm A) or greater than 6 weeks after registration (Arm B). 
 
 


S2011 
 
 
Page 29 
Version Date 03/09/2023 
 
 
 
7.5 
Discontinuation of Treatment 
 
All reasons for discontinuation of systemic treatment must be documented in the Off 
Systemic Treatment Notice. 
 
7.6 
Follow-Up Period 
 
All participants will be followed until death or 5 years after registration, whichever occurs 
first.  
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
8.2 
General Considerations  
 
a. 
No dose reductions are allowed for avelumab.  Dose delays are allowed as 
outlined below. 
 
b. 
The maximum systemic treatment dose delay for any reason is 21 days. 
 
c. 
Missed doses will not be made up. 
 
d. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction.  
 
e. 
Reductions are based on the dose being given at the end of the preceding cycle 
and are based on toxicities observed since the prior toxicity evaluation.  
 
f. 
If a drug must be permanently discontinued, the participant must be removed from 
protocol therapy. 
 
In order to provide optimal patient care, investigator discretion and institutional policies may 
be used in the prescribing of all supportive care drug therapy including, but not limited to 
antimicrobials, anti-emetics, G-CSF, PRBC, or platelet transfusion, etc.  Pre-medications 
used for standard treatments for carboplatin, gemcitabine, and if needed, for avelumab as 
per the package insert.   
 
The following criteria must be met within 3 days prior to starting day 1 of any cycle: 
 
ANC ≥ 1500 cells/mm3 
 
Hemoglobin > 9 g/dl 
 
Platelet ≥ 100,000/mm3 
 
Bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if Gilbert’s disease) 
 
Creatinine clearance ≥ 30 ml/min 
 
For Cycle 2 and beyond, Day 1 and Day 8 treatment may be given using a +/- 3-day 
window.  A treatment cycle may be delayed up to 5 days for inclement weather, major 
holiday, serious illness of a family member, or vacation that cannot be rescheduled without 
being a protocol deviation. 
 


S2011 
 
 
Page 30 
Version Date 03/09/2023 
 
 
If there is a treatment delay of > 21 days, participants will be removed from systemic 
protocol treatment. 
 
Supportive Care 
 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care.  During the study, 
supportive therapy can include antibiotics, analgesics, pain control, transfusions, 
psychotherapy, growth factors, hydration or any other symptomatic therapy as clinically 
indicated.  Steroids will be allowed to treat any immune-related adverse events from 
avelumab as outlined in Section 8.3 for management of immune-related adverse events.  
 
Treatment modification for symptoms of infusion-related reactions will be per institutional 
guidelines.  For severe/life threatening (Grade 3 or 4) avelumab related infusion reactions, 
discontinue avelumab and manage anaphylaxis per institutional guidelines.  
 
8.3 
Dose Modifications and Delays 
 
Carboplatin and gemcitabine 
 
Note:  Dose modification guidelines are recommendations not requirements.  Sites may 
use institutional guidelines if preferred.   
 
Up to 2 dose reductions are allowed for carboplatin and gemcitabine. Once dose is 
reduced, no subsequent escalations are recommended. If avelumab has to be held for 
toxicities, gemcitabine and carboplatin may continue with dose modifications if necessary, 
for gemcitabine/carboplatin related toxicities. 
 
Cycle 2 Day 1: The dose modification guidelines for gemcitabine and carboplatin for 
hematologic toxicity on Day 1 of Cycle 2 and subsequent cycles is mentioned below. 
 
ANC 
 
Platelet count
Gemcitabine
Carboplatin  
>1500/mm3 
And 
>100,000/mm3
Give 100% dose
Give 100% dose
< 1500/mm3 
and/or
<100,000/mm3
Delay treatment by 
1 week; Reduce 
dose for 
subsequent cycles 
by 25%
Delay treatment by 1 
week; Reduce dose 
for subsequent cycles 
by AUC=1 
 
The dose modification guidelines for gemcitabine and carboplatin for hematologic toxicity 
on Day 8 of Cycle 1 and subsequent cycles is mentioned below. 
 
 
 
 
 
 
 
 
 
 
 
Primary prophylaxis with G-CSF should be considered with subsequent cycles if 
participants develop neutropenic complications in the immediate previous cycle. If febrile 
neutropenia requiring antibiotic therapy or Grade 4 thrombocytopenia occurs, the 
gemcitabine dose will be reduced by 25% for subsequent treatment cycles. The dose of 
ANC 
Platelet count
Gemcitabine
≥1,000/mm3 
and 
≥ 75,000/mm3
Give 100% dose 
≥1,000/mm3 
and
50,000-74,999
Give 75% dose  
<1,000/mm3 
or
< 50,000/mm3
Skip treatment. Reduce dose  
by 25% for next treatment. 


S2011 
 
 
Page 31 
Version Date 03/09/2023 
 
 
carboplatin may be reduced by AUC=1 for subsequent treatment cycles at the discretion 
of treating physician.   
 
If a Day 8 gemcitabine is withheld due to hematologic toxicity, it will be skipped and not be 
given at a later date and the cycle will continue with Day 1 of the next cycle of treatment.   
 
Avelumab 
 
No dose modifications are permitted for avelumab.  
 
If gemcitabine and/or carboplatin are held for toxicities related to gemcitabine/carboplatin, 
avelumab may continue if no prohibitive toxicities related to avelumab are observed. 
Avelumab therapy should be continued with close monitoring for Grade 1 toxicities, with 
the exception of some neurologic, hematologic, and cardiac toxicities. 
  
Infusion-related reactions include pyrexia, chills, flushing, hypotension, dyspnea, 
wheezing, back pain, abdominal pain, and urticaria. The rate of infusion is interrupted or 
slowed for mild or moderate Grade 1-2 infusion-related reactions, with consideration of 
resuming the usual infusion-rate when symptoms revert to grade 1 or less. The infusion is 
stopped and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) 
infusion-related reactions  
 
Avelumab may be suspended for most Grade 2 toxicities including immune related adverse 
events. Grade 3 toxicities including immune related adverse events generally warrant 
suspension of avelumab. Permanent discontinuation of avelumab is recommended with 
Grade 4 toxicities, with the exception of endocrinopathies that have been controlled by 
hormone replacement.  
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 will be used to 
grade adverse events. A copy of the CTCAE Version 5.0 can be downloaded: 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quic
k_reference_5x7.pdf). Management of toxicities from gemcitabine and carboplatin will be 
per the package insert and standard institutional guidelines. The management of avelumab 
related immune adverse events are per physician discretion. Corticosteroids may be 
administered for Grade 2 toxicities. Grade ≥3 immune adverse events require the initiation 
of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 
mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some 
refractory cases may require infliximab or other immunosuppressive therapy.  
 
8.4 
White blood Cell Growth Factors 
 
If used, white blood cell growth factors, including biosimilars, must be used per ASCO 
guidelines (http://jco.ascopubs.org/content/24/19/3187.full) and NCCN Guidelines® 
Myeloid 
Growth 
Factors 
(http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf). 
 
8.5 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Sonpavde at 617/632-
2164 or Michael Liss at 210/567-1100.   
 
8.6 
Adverse Event/Serious Adverse Event Reporting Guidance 
 
 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of post-baseline Adverse Events (AE) entered in 
Rave to determine whether they require expedited reporting and facilitates entry in CTEP-
AERS for those AEs requiring expedited reporting.    
 


S2011 
 
 
Page 32 
Version Date 03/09/2023 
 
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period and used to collect 
AEs that start during the period or persist from the previous reporting period. CRA will enter 
AEs that occur prior to the start of treatment on a baseline form that is not included in the 
Rave-CTEP-AERS integration. AEs that occur prior to enrollment must begin and end on 
the baseline Adverse Events form and should not be included on the standard Adverse 
Events form that is available at treatment unless there has been an increase in grade. 
 
Prior to sending AEs through the rule’s evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
The reporting period (course/cycle) is correct; and 
 
AEs are recorded and complete (no missing fields) and the form is query 
free.  
 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and protocol-
specific reporting rules evaluate the AEs submitted for expedited reporting. A report is 
initiated in CTEP-AERS using information entered in Medidata Rave for AEs that meet 
reporting requirements. The CRA completes the report by accessing CTEP-AERS via a 
direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be made 
to SWOG by telephone at 210-614-8808. Once internet connectivity is restored, the 24-
hour notification that was phoned in must be entered immediately into CTEP-AERS using 
the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU website: 
 
Study specific documents: Protocols > Documents> Education and Promotion; 
and   
 
Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides & Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ae
guidelines.pdf. 
 
If you have questions about this process, please contact the SAE Program Manager 210-
614-8808 or email adr@swog.org. 
 
8.7 
 Adverse Events Related to COVID-19 
 
Infections occurring in participants on clinical trials are considered adverse events and 
should be reported per protocol guidelines via normal procedures (on CRFs/Rave and via 
CTEP-AERS if serious).  
 
Please document COVID-19 related adverse events as follows:  
 
Infections and infestations - Other, specify  
Specify = COVID-19  
 


S2011 
 
 
Page 33 
Version Date 03/09/2023 
 
 
Additionally, please record (and if applicable, report via CTEP-AERS) any other Adverse 
Events the subject experiences such as Dyspnea, Acute respiratory distress syndrome, 
etc.  
 
CTEP-AERS specific instructions:  
 
 
Narrative: Identify all pertinent facts related to the COVID-19 infection including, 
but not limited to the following:  
o 
Presumptive vs confirmed diagnosis. If presumptive, please update your 
narrative if/when diagnosis is confirmed, including timelines.  
o 
Treatment information  
o 
Recovery information, including timelines  
o 
Outcome information/status 
 
Supporting documentation: Please fax supporting documentation including 
admission notes, progress notes, clinical visits, and discharge summary if/when 
available.  
o 
Fax Number: 301-897-7404, include protocol number, ticket number and 
subject ID on the fax cover sheet and each page faxed.  
 
Queries:  
CTEP-AERS Questions/Help:
Email: ctephelpdesk@nih.gov  
Phone: 1-888-283-7457 
 
8.8 
Serious Adverse Event Reporting Requirements  
 
a. 
Definition and Purpose 
 
Definition:  Adverse event means any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related (FDA, 21 
CFR 312.32). See Table 8.1 for definition of a Serious Adverse Event (SAE) and 
reporting requirements. 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of participants 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 
participant safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol.  
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported to SWOG 
Operations Office 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. 
 
NOTE:  For this study, all adverse events requiring expedited reporting must 
initially be reported on the Adverse Event Form in the appropriate Treatment 
Cycle folder in Medidata Rave.  The CTEP-AERS report must then be initiated 
directly from the Adverse Event Form in Medidata Rave.  Do not initiate the 
CTEP-AERS report via the CTEP-AERS website. 
 
c. 
When to report an event in an expedited manner 
 


S2011 
 
 
Page 34 
Version Date 03/09/2023 
 
 
Some adverse events require 24-hour notification (refer to Table 8.1) via CTEP-
AERS.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to SWOG by telephone at 210-614-8808 or by email adr@swog.org .  An 
electronic report MUST be submitted immediately upon re-establishment of 
internet connection. 
 
When the adverse event requires expedited reporting, submit the report via CTEP-
AERS within the number of calendar days of learning of the event specified in 
Table 8.1.   
 
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 participant must be reported according to local 
policy and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the participant has received at least one dose of 
the investigational agent(s) as part of the trial. Reporting requirements are 
provided in Table 8.1.  The investigational agent used in Arm A of this study is 
avelumab.  If there is any question about the reportability of an adverse event or if 
Internet connectivity is disrupted on-line please telephone or email the SAE 
Program Manager at the Operations Office, 210/614-8808 or adr@swog.org, 
before preparing the report. 
 
NOTE: For this study, all adverse events requiring expedited reporting must 
initially be reported on the Adverse Event Form in the appropriated 
Treatment Cycle folder in Medidata Rave.  Once the adverse event is entered 
into RAVE, the Rules Engine will confirm whether or not the adverse event 
requires expedited reporting.  The CTEP-AERS report must then be initiated 
directly from the Adverse Event Form in Medidata Rave.  Do not initiate the 
CTEP-AERS report via the CTEP-AERS website.  Sites are encouraged to 
confirm the Expedited Reporting Evaluation Recommendation with the 
reporting criteria outlined in Table 8.1. 
 
 
Table 8.1 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a Non-CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1  [Avelumab] ([Arm A]). 


S2011 
 
 
Page 35 
Version Date 03/09/2023 
 
 
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 participant 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 
Timeframes 
Grade 2 
Timeframes
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in Section 
8.6f.   
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 30 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 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 Grade 1-2 adverse events resulting in hospitalization or prolongation of hospitalization  
 Grade 3 adverse events 
 
 
May 5, 2011 
 
f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under 
a non-CTEP-IND: 
 
1. 
Group-specific instructions. 
 


S2011 
 
 
Page 36 
Version Date 03/09/2023 
 
 
Supporting Documentation Submission – Within 5 calendar days submit 
documentation supporting the CTEP-AERS report to the SWOG 
Operations Office by fax 210-614-0006. Specific instructions will be sent 
by email to the reporting site by the SAE Program Manager. 
 
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
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. 
 
SWOG requires all secondary malignancies that occur following treatment 
with an agent under a Non-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.  
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  
 
2. 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  Supporting 
documentation must also be submitted to SWOG Operations Office by fax 
to 210-614-0006.    
              
NOTE: If a participant 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 participants 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 


S2011 
 
 
Page 37 
Version Date 03/09/2023 
 
 
“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 participant 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 participant 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 210-614-0006.  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    
 
 


S2011 
 
 
Page 38 
Version Date 03/09/2023 
 
 
9.0 
STUDY CALENDAR 
 
9.1 
Arm A:  Gemcitabine + Carboplatin + Avelumab + Surgery 
   
PRE- 
REG  
 
Cycle 1 
 
Cycle 2 
Cycle 3 
Cycle 4 
At end of 
systemic 
therapy 
4-8 
weeks 
post 
systemic 
therapy  
 
90 days 
post 
surgery 
At 
progression
/recurrence 
Follow up 
after 
progression
/recurrence 
W 
1  
W 
2 
W 
3 
W
4 
W
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10 
W 
11 
W 
12 
 
(Each cycle = 21 days) 
 
PHYSICAL 
 
History & Physical 
Exam  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
Weight & Zubrod 
Performance 
Status  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
Disease 
Assessment (A) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Every 12 weeks 
following surgery for 
years 1-2, every 6 
months for year 3, then 
annually in years 4-5
Annually 
Toxicity Notation  
X 
XG 
XG 
XG 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
LABORATORY  
 
Pregnancy test 
(urine or blood) in 
women of child-
bearing potential 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
Metabolic Panel B  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Complete blood 
cell counts (Hb, 
hematocrit, WBC, 
ANC (absolute 
neutrophil count), 
platelet 
 
X 
X 
X 
 
X
X
X
X
X
X
 
 
 
 
 
X 
 
X
 
 
TSH, free T4 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 


S2011 
 
 
Page 39 
Version Date 03/09/2023 
 
 
SURGERY 
Radical Cystectomy 
or 
Nephroureterectomy 
or Ureterectomy  
 
 
 
 
X 
 
 
SPECIMEN SUBMISSION (see Section 15.1) (F)  
Archival tissue  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Whole blood & buffy 
coat 
 
X  
 
 
 
 
 
 
 
 
 
 
 
X(D)
X 
 
 
Urine  
 
X  
 
 
 
 
 
 
 
 
 
 
 
X(D) 
 
 
 
 
Tissue from surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
TREATMENT 
Gemcitabine 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
Carboplatin 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Avelumab 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Click here for Footnotes 
 
 
   
PRE- 
REG  
 
Cycle 1 
 
Cycle 2 
Cycle 3 
Cycle 4 
At end of 
systemic 
therapy 
4-8 
weeks 
post 
systemic 
therapy  
 
90 days 
post 
surgery 
At 
progression
/recurrence 
Follow up 
after 
progression
/recurrence 
W 
1  
W 
2 
W 
3 
W
4 
W
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10 
W 
11 
W 
12 
 
(Each cycle = 21 days)
 
SCANS 
 
CT scan chest, 
CT or MRI 
abdomen, CT or 
MRI pelvis with 
contrast (C) 
X (E) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Every 12 weeks 
following surgery for 
years 1-2, , every 6 
months for year 3, then 
annually in years 4-5 
 


S2011 
 
 
Page 40 
Version Date 03/09/2023 
 
 
9.2 
Arm B:  Surgery Only 
 
  
PRE- 
REG  
Within 6 
weeks of 
registration 
90 days  
post-surgery 
At progression/ 
recurrence 
Follow up after 
progression/recurrence 
PHYSICAL 
 
History & Physical Exam  
X 
X 
X 
 
 
Weight & Zubrod Performance Status  
X 
X 
X 
 
 
Disease Assessment (A) 
X 
 
Every 12 weeks following surgery for 
years 1-2, every 6 months for year 3, 
then annually in years 4-5
Annually 
Toxicity Notation 
X 
X 
X 
 
 
Follow up after prog? 
 
 
 
 
 
LABORATORY  
 
Pregnancy test (urine or blood) in women of 
child-bearing potential 
X 
 
 
 
Complete Metabolic Panel B 
X 
 
 
 
Complete blood cell counts (Hb, hematocrit, 
WBC, ANC (absolute neutrophil count), platelet
X 
 
 
 
TSH, free T4 
X 
 
 
 
SCANS 
 
CT scan chest, abdomen, pelvis with contrast (C) 
X (E) 
Every 12 weeks following surgery for 
years 1-2, , annually in years 3-5 
 
SURGERY 
 
Radical Cystectomy, Nephroureterectomy or 
Ureterectomy 
 
X 
 
 
 
SPECIMEN SUBMISSION (see Section 15.1) (F) 
 
Archival tissue  
X 
  
 
 
Whole blood & buffy coat 
X (D)
X 
Urine  
 
X (D) 
 
 
 
Tissue from surgery 
 
X 
 
 
 
Click here for Footnotes   
 
 


S2011 
 
 
Page 41 
Version Date 03/09/2023 
 
 
 
Footnotes for 9.1 and 9.2: 
 
A  
CT/MRI abdomen and pelvis, and x-ray/CT chest  
B 
CMP to include (at minimum):  Bilirubin, AST and ALT, alkaline phosphatase, and serum creatinine 
C 
Participants with renal dysfunction who cannot receive contrast are recommended to undergo CT chest without contrast and MRI abdomen 
and pelvis with gadolinium 
D 
Collect prior to surgery 
E 
Bone scan if high alkaline phosphatase or suspected bone pain 
F 
With participant consent 
G 
Submit Adverse Event form in Rave WEEKLY for the first cycle (3 weeks), for first 20 patients on Arm A 
 


S2011 
 
 
Page 42 
Version Date 03/09/2023 
 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Pathologic complete remission  
 
Pathologic complete remission (pCR) is defined as absence of all disease in the surgical 
specimen from radical cystectomy, nephroureterectomy or ureterectomy as determined by 
the pathologist at the institution, i.e. ypT0N0 disease. Those without a surgical specimen 
will assume to be non-responders. 
 
10.2 
Event-free Survival (EFS) 
 
Event-free survival is defined as the time from randomization to the first EFS event.  For 
those who do not undergo surgery, event time will be assigned to the date of disease 
assessment that indicated surgery was no longer indicated or physician decision not to 
conduct the surgery.   
 
An EFS event is defined as: any of the following events:  
 
 
Progression of disease during the neoadjuvant period for which surgical resection 
is no longer indicated. 
 
If surgery is attempted but gross resection is abandoned due to unresectable 
tumor.  
 
If surgery is possible, but not performed for other reasons. 
 
If surgery is completed with positive soft tissue margins.  
 
Post-surgical high grade upper tract or muscle invasive bladder cancer.  
 
Post-surgical distant recurrence (biopsy of indeterminate lesions should be 
performed when feasible).  
 
Death due to any cause. 
 
10.3 
Recurrence  
 
Imaging intervals are every 3 months for 2 years, then annually in years 3-5. The date of 
recurrence is the time at which specific radiologic criteria are met. Recurrence can also be 
dated to the time of a positive biopsy, if available, or at the time of investigator-assessed 
clinical progression. When a radiologic and histopathologic diagnosis date are both 
available, the date of radiologic diagnosis is preferred, because biopsies are typically 
prompted by preceding radiologic findings.  
 
10.4 
Performance Status:  Participants 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.   


S2011 
 
 
Page 43 
Version Date 03/09/2023 
 
 
10.5 
Dose Limiting Toxicities (DTLs) 
 
 
Any death not clearly due to the underlying disease or extraneous causes 
 
Hy's law  
 
Neutropenic fever  
 
Any grade 3+ non-hematologic toxicity 
 
Grade 4+ neutropenia or thrombocytopenia >7 days 
 
Grade 3+ thrombocytopenia with bleeding  
 
Grade 3+ nausea/vomiting or diarrhea >72 hours with adequate antiemetic and 
other supportive care 
 
Grade 3+ fatigue ≥ 1 week 
 
Grade 3+ electrolyte abnormality that lasts >72 hours, unless the patient has 
clinical symptoms, in which case all grade 3+ electrolyte abnormality regardless of 
duration should count as a DLT.  Grade 3+ amylase or lipase elevation NOT 
associated with symptoms or clinical manifestations of pancreatitis does not need 
to be counted as a DLT. 
 
All AEs of the specified grades should count as DLTs except those that are clearly 
and incontrovertibly due to disease progression or extraneous causes. 
 
For patients with hepatic metastases, AST or ALT >8xULN or AST or ALT >5x ULN 
for ≥14 days 
 
Discontinuation of treatment should be considered if: 
- ALT or AST >8xULN 
- ALT or AST >5xULN for more than 2 weeks 
- ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 
- ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
The primary objective of this open label comparative randomized phase II multicenter trial with 1:1 
randomization is to compare pathologic complete response as the primary endpoint. A dynamic 
balancing algorithm will be used to randomize participants in a 1:1 ratio to the two arms based on 
the three stratification factors (clinical stage, performance status and creatinine clearance). All 
eligible, randomized participants will be assessed for the primary outcome regardless of amount of 
neoadjuvant treatment received in an ITT analysis. Those participants not undergoing protocol 
surgery will be assumed to be non-responders. With 178 evaluable participants, the trial will have 
a power of 90% (using a 1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. 
This increment in pCR rate is hypothesized to be highly likely to translate to improved PFS and OS, 
given the results of SWOG S8710.  To account for a 10% ineligible rate, the total accrual goal is 
196 randomized participants.   
 
11.1  
Estimate of Sample Size and Accrual Rate 
 
With 178 evaluable participants, the trial will have a power of 90% (using a 1-sided alpha 
0.05) to detect pCR rate improvement from 15% to 35%. This increment in pCR rate is 
hypothesized to be highly likely to translate to improved PFS and OS, given the results of 
SWOG S8710.  To account for a 10% ineligible rate, the total accrual goal is 196 
randomized participants.   
 
Based on accrual to previous SWOG neoadjuvant therapy and radical cystectomy focused 
bladder cancer trials (S8710, S1314, S1011), and the increased momentum behind the 
use of immunotherapy and neoadjuvant chemotherapy for muscle invasive bladder cancer, 
we anticipate an accrual rate of 8 participants per month. We anticipate full accrual will take 
2.0 years.   
 
 


S2011 
 
 
Page 44 
Version Date 03/09/2023 
 
 
 
11.2  
Analysis Plan 
 
There will be one safety and one futility interim analysis conducted when the first half of 
the participants have been enrolled and evaluated on both arms for pathologic response.  
If the complete pathologic response rate for the neoadjuvant therapy followed by surgery 
arm is smaller than that for surgery alone then we will conclude futility and close the study. 
 
The safety analysis will be conducted in the first 20 patients on Arm A. These patients will 
be evaluated more intensively for adverse events, with AE assessment data submitted 
weekly for the first cycle (3 weeks). Although there will be a global approach to AE 
assessment, we will focus particularly on DLTs. If 7 (35%) or more of the first 20 evaluable 
patients on the experimental arm experience DLTs, then consideration will be given to 
reevaluating the safety and feasibility of the experimental regimen. Detailed listings of 
toxicities and supportive data will be evaluated by the study team, the study DSMC and 
CTEP. 
 
The futility analysis will be conducted when the first half of the participants have been 
enrolled and evaluated on both arms for pathologic response.  If the complete pathologic 
response rate for the neoadjuvant therapy followed by surgery arm is smaller than that for 
surgery alone then we will conclude futility and close the study. 
 
The final analysis of the primary objective will be conducted after all participants have been 
evaluated for path response.  A logistic regression model will be fit to path CR as the 
outcome and will include stratification factors as covariates in the model.  If the one-sided 
p-value is less than or equal to 0.05 for the neoadjuvant treatment arm odds ratio then we 
will conclude a statistically significant result.   
 
For the secondary event-free survival endpoint (see Section 10.0), with 89 eligible 
participants per arm, 2 years of accrual and 3 additional years of follow-up, and assuming 
a median EFS on the surgery alone arm of 24 months, which is expected based on the 
median disease-free survival on the control arm of the MRC trial (2), the trial will also have 
power of 80% to detect an increase in the median EFS with the addition of the neoadjuvant 
regimen of 12 months, for a median of 36 months (equivalent to a hazard ratio of 0.667) 
using a one-sided alpha=0.10.  
 
Timeline 
Surgery Only 
NAC + surgery
 
Statistical 
Power for 
EFS** 
Type I Error 
Rate for EFS 
Accrual 
completed 
89 
participants
enrolled
89 
participants
enrolled
 
Six months post-
accrual 
Analysis of primary objective,
pT0 rate comparison between arms
N/A 
N/A 
 
Median 
Assumed to be 
24 months
Median Assumed to 
be 36 months 
 
1 
year 
post-
accrual 
completion 
# of EFS events 
= 44 
# of EFS events = 
32 
0.71 
0.10
2 
year 
post-
accrual 
# of EFS events 
= 57 
# of EFS events = 
44 
0.79 
0.10
3 
years 
post-
accrual 
# EFS events = 
66 
# of EFS events = 
53 
0.84 
0.10
** if primary EFS analysis conducted at the given time point.
 
 
 


S2011 
 
 
Page 45 
Version Date 03/09/2023 
 
 
 
11.3  
Adverse Event Monitoring 
 
The study chair, statisticians and data coordinator(s) will review summary reports on a 
monthly basis which include adverse events by arm, treatment dose modifications, and 
reasons for discontinuation of protocol treatment. Serious adverse events are reviewed by 
the study team immediately after receiving notification. Additionally, the study chair will be 
reviewing patient data via our Study Chair Evaluation system on an ongoing basis 
throughout the study. 
 
11.4 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG Cancer Research 
Network, three SWOG members, three 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 six 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. 
 
 
12.0 
DISCIPLINE REVIEW 
 
There is no discipline review for this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Arm A: Initiation of systemic treatment must be planned to start no more than 14 calendar 
days after registration. 
 
Arm B: Surgery must be planned to occur within 6 weeks after registration 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a participant 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. 
 
13.3 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and require sponsors to select 
qualified investigators. National Cancer Institute (NCI) policy requires all 
individuals contributing to NCI-sponsored trials to register andwith their 
qualifications and credentials and to renew their registration annually. To register, 
all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity 
and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In 
addition, persons with a registration type of Investigator (IVR), Non-Physician 
Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository 
(RCR) at https://ctepcore.nci.nih.gov/rcr.   Investigators and clinical site staff who 
are significant contributors to research must register in the Registration and 
Credential Repository (RCR). The RCR is a self-service online person registration 
application with electronic signature and document submission capability. 


S2011 
 
 
Page 46 
Version Date 03/09/2023 
 
 
RCR utilizes five-person registration types. 
 
Investigator (IVR) — MD, DO, or international equivalent; 
 
Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) 
or graduate level researchers (e.g., PhD); 
 
Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the Roster Update Management System (RUMS), OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required
IVR
NPIVR
AP 
A 
AB
FDA Form 1572 


 
 
Financial Disclosure Form


 
 
NCI 
Biosketch 
(education, 
training, 
employment, license, and certification)


 
 
GCP training 


 
 
Agent Shipment Form (if applicable)

 
 
CV (optional) 


 
 
 
An active CTEP-IAM user account with a linked ID.me account (the latter required 
immediately for new CTEP-IAM accounts, and appropriate RCR registrationby July 1, 2023 
for all users) is required to access all CTEP and participate in NCI clinical trials supported 
by the Cancer Trials Support Unit (CTSU) and to access all CTEP and CTSU websites and 
applications. In addition, IVRs and NPIVRs must list all clinical practice sites and 
Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
 
 
Addition to a site roster 
 
Selection as the treating, credit, consenting, or drug shipment (IVR only) 
investigator or consenting person in OPEN Ability to be named as the site-protocol 
Principle (PI) on the IRB approval; and 
 
Assignment the Clinical Investigator (CI) task on the Delegation of Tasks Log 
(DTL).     
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
 
Additional information is located 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.govmailto:.  
 
13.4 
CTSU Registration Procedures 
 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on the person and site roster assignment housed in the Roster Maintenance 
application and in most cases viewable and manageable via the Roster Update 
Management System (RUMS) on the Cancer Trials Support System (RSS).Unit (CTSU) 
members’ website. 
This study is supported by the NCI CTSU. 
 
a. 
IRB Approval:   
 


S2011 
 
 
Page 47 
Version Date 03/09/2023 
 
 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies 
open to the National Clinical Trials Network (NCTN) and NCI Community Oncology 
Research Program (NCORP) Research Bases. In addition, U.S.-based sites must 
accept the NCI CIRB review to activate new studies at the site after March 1, 2019. 
Local IRB review will continue to be accepted for studies that are not reviewed by 
the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) 
approval to the CTSU Regulatory Office following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open 
the study locally. 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. The NCI CIRB’s approval of the 
SSW is automatically communicated to the CTSU Regulatory Office, but sites are 
required to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org 
to establish site preferences for applying NCI CIRB approvals across their 
Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria  for the site to be able to have 
an Approved status following processing of the IRB/REB approval record: 
 
Have an active CTEP status; 
 
Have an active status at the site(s) on the IRB/REB approval (applies to 
US and Canadian sites only) on at least one participating organization’s 
roster; 
 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable 
CIRB Signatory Institution(s) record; 
 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; 
 
 List all sites on the IRB/REB approval as Practice Sites in the Form FDA 
1572 in the RCR profile; and 
 
Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
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 Protocol Organization (LPO) or a 
Participating Organization (PO); and 
 
Compliance with all applicable protocol-specific requirements (PSRs). 
 
b. 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and their associated investigators 
and staff on a participating roster. To view/download site registration forms:   
 
Log in to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password or linked ID.me account (ID.me 
accounts are required for all newly created CTEP-IAM accounts and by 
July 1, 2023 for all users); 


S2011 
 
 
Page 48 
Version Date 03/09/2023 
 
 
 
Click on Protocols in the upper left of the screen 
o 
Enter the protocol number in the search field at the top of the 
protocol tree; or 
o 
Click on the By Lead Organization folder to expand, then select 
SWOG and protocol number S2011.  
 
Click on Documents, select Site Registration, and download and complete 
the forms provided. (Note: For sites under the CIRB, IRB data will load 
automatically to the CTSU.)  
 
c. 
Submitting Regulatory Documents:  
. 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, 
go to the Regulatory section and select Regulatory Submission. 
 
Institutions with participants waiting that are unable to use the Regulatory 
Submission Portal should alert the CTSU Regulatory Office immediately at 1-866-
651-2878 in order to receive further instruction and support. 
 
d. 
Checking Your Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.  
 
Click on Regulatory at the top of the screen; 
 
Click on Site Registration; and 
 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o 
Additional filters are available to sort by Protocol, 
Registration Status, Protocol Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with NCI or their affiliated networks. 
 
e. 
Delegation of Task Log (DTL) 
 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using 
the DTL application in the Delegation Log section on the CTSU members’ website. 
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 
participants to the study. To maintain an approved site registration status the CI 
must re-sign the DTL at least annually and when a new version of the DTL is 
released; and activate new task assignments requiring CI sign-off. Any individual 
at the enrolling site on a participating roster may initiate the site DTL. Once the DTL 
is submitted for CI approval, only the designated DTL Administrators or the CI may 
update the DTL. Instructions on completing the DTL are available in the Help Topics 
button in the DTL application and describe DTL task assignments, CI signature, 
and CTEP registration requirements, as well as include a Master Task List. 
 
13.5 
Oncology Patient Enrollment Network (OPEN) Registration Requirements 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of participant registration/randomization 


S2011 
 
 
Page 49 
Version Date 03/09/2023 
 
 
assignment. OPEN will populate the participant enrollment data in NCI’s clinical data 
management system, Medidata Rave. 
 
Requirements for OPEN access:   
 
A valid CTEP-IAM account and linked ID.me account (ID.me accounts are 
required for all newly created CTEP-IAM accounts and by July 1, 2023 for all 
users);; 
 
To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role 
of Registrar. Registrars must hold a minimum of an Associate Plus (AP) 
registration type; 
 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must 
hold the OPEN Registrar task on the DTL for the site; and 
 
Have an approved site registration for the protocol prior to participant 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a participant 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
 
 
Participant has met all eligibility criteria within the protocol stated timeframes; 
and  
 
All participants have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. You may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.6 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Participants 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 participants 
registered, whether or not assigned treatment is administered, including 
participants deemed to be ineligible.  Participants for whom documentation is 
inadequate to determine eligibility will generally be deemed ineligible 
 
14.2 
Master Forms 
 


S2011 
 
 
Page 50 
Version Date 03/09/2023 
 
 
Master forms can be found on the protocol page on www.swog.org the CTSU website 
(www.ctsu.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. 
 
14.3 
Data Submission Procedures 
 
a. 
Medidata Rave is the clinical data management system being used for data 
collection for this trial/study. Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments.  
 
Requirements to access Rave via iMedidata: 
 
A valid CTEP-IAM account and linked ID.me account (ID.me accounts are 
required for all newly created CTEP-IAM accounts and by July 1, 2023 for 
all users);; and  
 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.  
 
 
 
Rave role requirements: 
o 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum 
of an Associate Plus (AP) registration type; 
o 
Rave Investigator role must be registered as a Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
o 
Rave Read Only or Rave SLA role must have at a minimum an 
Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those 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 the Regulatory application, 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 staff must log in to 
the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM 
username and password and click on the accept link in the upper right-corner of 
the iMedidata page. Site staff 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. If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study 
name in iMedidata instead of the Rave EDC link; once the successful completion 
of the eLearning has been recorded, access to the study in Rave will be granted, 
and a Rave EDC link will display under the study name.  
 
Site staff who have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in the Regulatory application 
will receive a separate invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website in the Data Management 
section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is 
available on the CTSU members’ website in the Data Management > Rave section 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com.   
  


S2011 
 
 
Page 51 
Version Date 03/09/2023 
 
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org).  
 
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. 
 
d. 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Site staff should review the 
DQP modules on a regular basis to manage specified queries and delinquent 
forms. 
 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data via direct links available in the DQP modules. 
 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, and DQP Delinquent Forms 
modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for delinquent 
form details and reports to be available on the DQP. Site staff should contact the 
LPO Data Manager for their protocol regarding questions about Rave Calendar 
functionality. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 15 DAYS AFTER REGISTRATION:    
  
Submit the following: 
 
Vital Status form 
 
Onstudy Forms 
 
Documentation that participant is deemed a surgical candidate (uploaded as a 
source document in Rave) 
 
Pathology Report from TURBT or ureteroscopic biopsy of the UTUC (upload as a 
source document in Rave) 
 
Submit scan reports from all scans performed to assess disease at Pre-
registration. (uploaded as source documents in Rave) 
 
Blood and Urine specimens as outlined in Section 15.0 


S2011 
 
 
Page 52 
Version Date 03/09/2023 
 
 
 
b. 
WITHIN 30 DAYS AFTER REGISTRATION: 
 
Submit the following: 
 
Archival tissue specimens as outlined in Section 15.0 
 
c. 
WITHIN 7 DAYS FOLLOWING EACH OF WEEKS 1 – 3 (WEEKLY 
SUBMISSIONS IN CYCLE 1)  - FIRST 20 PATIENTS IN ARM A ONLY 
 
Vital Status Form 
 
Adverse Event Form 
 
Treatment Form (submit once, at the end of the cycle/week 3) 
 
 


S2011 
 
 
Page 53 
Version Date 03/09/2023 
 
 
 
d. 
WITHIN 15 DAYS AFTER EACH CYCLE OF SYSTEMIC TREATMENT (ARM A 
ONLY) 
* for the first 20 patients on Arm A, this section applies to cycles 2 and beyond 
 
Submit the following: 
 
Vital Status Form 
 
Treatment Form  
 
Adverse Event Form 
 
e. 
WITHIN 15 DAYS AFTER DISCONTINUATION OR COMPLETION OF 
SYSTEMIC TREATMENT (ARM A ONLY): 
 
Submit the following: 
 
Vital Status Form 
 
S2011 Off Systemic Treatment Notice 
 
Final Treatment Form 
 
Adverse Event Form 
 
Blood and Urine specimens as outlined in Section 15.0 
 
f. 
WITHIN 15 DAYS AFTER DECISION TO NOT PERFORM PROTOCOL 
SURGERY OR 8 WEEKS AFTER LAST NEOADJUVANT THERAPY (whichever 
occurs first) ARM A ONLY: 
 
Vital Status Form 
 
S2011 Surgery Status Form 
 
g. 
WITHIN 15 DAYS AFTER DECISION TO NOT PERFORM PROTOCOL 
SURGERY OR 6 WEEKS AFTER REGISTRATION (whichever occurs first) ARM 
B ONLY: 
 
Vital Status Form 
 
S2011 Surgery Status Form 
 
h. 
WITHIN 15 DAYS AFTER PROTOCOL SPECIFIED SURGERY (ARMS A & B) 
 
Vital Status Form 
 
S2011 Surgery Status Form 
 
S2011 Surgery Reporting Form 
 
Operative Report (uploaded as a source doc in Rave) 
 
Pre-surgery blood and urine specimens as outlined in Section 15.0 
 
i. 
WITHIN 30 DAYS AFTER PROTOCOL SPECIFIED SURGERY (ARMS A & B) 


S2011 
 
 
Page 54 
Version Date 03/09/2023 
 
 
 
Surgical tissue specimens as outlined in Section 15.0 
 
j. 
WITHIN 15 DAYS AFTER 90-DAY POST-SURGERY ASSESSMENT (ARMS A & 
B) 
 
Vital Status Form 
 
S2011 90 Day Post-Surgery Form 
 
Adverse Assessment form 
 
Blood specimen as outlined in Section 15.0 
 
k. 
WITHIN 
30 
DAYS 
AFTER 
EACH 
DISEASE 
ASSESSMENT 
UNTIL 
PROGRESSION: 
 
Submit the following: 
 
Vital Status Form 
 
Follow Up Form 
 
Submit scan reports from all scans performed to assess disease. (uploaded as 
source documents in Rave) 
 
l. 
WITHIN 15 DAYS OF PROGRESSION/RELAPSE: 
 
Vital Status Form  
 
Follow-Up Form (documenting date, site and method for determining 
progression/relapse). 
 
m. 
FOLLOWING PROGRESSION, Within 30 days of EVERY Follow-up (Annually 
until 5 years from registration) 
 
Submit the following: 
 
Vital Status Form 
 
Follow Up Form 
 
Late Adverse Events (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the participant experiences any 
severe [Grade ≥ 3] adverse event that is possibly, probably, or definitely related to 
protocol treatment, or a Serious Adverse Event [SAE] of any grade/attribution, that 
has not been previously reported). 
 
n. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and a final Follow-Up Form documenting death 
information. 
 
 


S2011 
 
 
Page 55 
Version Date 03/09/2023 
 
 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Specimens for Banking (REQUIRED with Participant Consent) 
 
Specimens for banking (submitted to the SWOG Biospecimen Bank–Solid Tissue, 
Myeloma and Lymphoma Division, Lab #201) (Optional for Participants): 
 
With participant consent, the following specimens must be submitted. 
 
a. 
Formalin-fixed paraffin embedded (FFPE) tissue 
 
1. 
Submitted at the following timepoints: 
 
 
Tumor tissue from baseline (archival) transurethral resection of 
bladder tumor (TURBT) or upper tract biopsy from endoscopic 
biopsy for all participants must be submitted within 30 days after 
registration.  
 
 
Tissue 
from 
radical 
cystectomy, 
nephroureterectomy, 
or 
ureterectomy must be submitted within 30 days after surgery.   
 
2. 
FFPE Tissue Specimen Collection and Submission Instructions 
 
Submit either:  
o 
One (1) block with tumor tissue or  
o 
One (1) H&E slide from each source block and ten (10) 4 
m unstained tissue on charged slides and five (5) 10 m 
unstained tissue on uncharged slides. If slides are limited, 
we prefer prioritization of the 10 m unstained slides.  We 
appreciate that for TURBT or upper tract biopsy, this 
tissue may be limited.  
 
 
Blocks or slides must be shipped at ambient temperature. 
 
 
Refer to the tissue labeling and submission instructions on the 
SWOG Specimen Submission webpage:  
 
 
(https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-procedures).   
 
 
Specimen collection kits are not provided for this submission; sites 
will use institutional supplies. 
 
b. 
Whole blood & Buffy Coat 
 
1. 
Submitted at the following timepoints: 
 
Arm A 
 
Prior to start of systemic treatment 
 
After end of systemic treatment, prior to surgery 
 
90 days post surgery 
 
Arm B 
 
Prior to surgery 
 
90 days post surgery 
 


S2011 
 
 
Page 56 
Version Date 03/09/2023 
 
 
2. 
Blood Collection and Submission Instructions 
 
 
Draw one (1) 10mL EDTA (lavender top) tube at each time point 
 
 
Draw one (1) 10 mL green-top (heparin) tube blood at each time 
point: 10 ml must be collected into a heparin tube at the specified 
time points. Blood should be processed for buffy coat as outlined 
on 
the 
SWOG 
Specimen 
Submission 
webpage 
(https://www.swog.org/member-resources/biospecimen-
resources) and stored at -70º C until shipped. Specimen collection 
kits are not being provided for this submission; sites will use 
institutional supplies. 
 
 
Follow packaging and shipment instructions on the SWOG 
specimen Submission webpage located at the following URL: 
https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-procedures  
 
 
EDTA tubes and green-top (heparin) tubes may be batch 
shipped on dry ice (every 3 months) 
 
3. 
Streck Tube (10 ml) at each time point 
 
 
Streck tubes will be provided by the study. Immediately after 
patient registration, order a ctDNA Streck tube kit via the following 
URL: https://kits.bpc-apps.nchri.org . Orders placed by noon 
Eastern should be received within 3-4 business days.  
 
 
NOTE: Streck tubes cannot be frozen and should not be batch 
shipped. 
 
c. 
Urine 
 
1. 
Submitted at the following timepoints: 
 
Arm A 
 
Prior to start of systemic treatment 
 
After end of systemic treatment, but prior to surgery 
 
Arm B 
 
Prior to surgery 
 
2. 
Urine collection and submission instructions 
 
 
Collect 50 ml urine 
 
Aliquot collected urine into 15 cc conical tubes, centrifuge 10 
minutes at 1,000 g (4ºC)  
 
Split pellet and supernatant into separate conical tubes and then 
freeze (-80 ºC) until shipment.   
 
Urine may be batch-shipped every 3 months on dry ice.  Ship to the 
SWOG Biospecimen Bank – Solid Tissue (Lab #201). 
 
15.2 
SHIPPING SAMPLES 
 
a. 
SWOG Specimen Tracking System (STS) 
 


S2011 
 
 
Page 57 
Version Date 03/09/2023 
 
 
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) Non- SWOG users may log into SpecTrack using their 
CTSU UserID and password on the SpecTrack login page located at  
https://spectrack.crab.org (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 must be printed and placed in the pocket of the specimen bag if it has one, 
or in a separate resealable bag. The participant ID must be included on any source 
documentation included with the shipment. 
 
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 
(https://spectrack.crab.org); or contact the SWOG Statistics and Data 
Management Center at 206/652-2267 to be routed to the Data Coordinator for 
further assistance. 
 
b. 
Federal guidelines for the shipment of blood products: 
 
1. 
The tube must be wrapped in an absorbent material. 
 
2. 
The tube must then be placed in an AIRTIGHT container (like a resealable 
bag). 
 
3. 
Pack the resealable bag and tube in a Styrofoam shipping container. 
 
4. 
Pack the Styrofoam shipping container in a cardboard box. 
 
5. 
Mark the box "Biohazard". 
 
 
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.  The model consent forms created for this study were modeled after the NCI 
informed consent template.   
 
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 


S2011 
 
 
Page 58 
Version Date 03/09/2023 
 
 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
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.  
 
The provision of Avelumab at no cost by EMD Serono / Merck KGaA for this study does not 
constitute an inducement to recommend, prescribe, purchase, or administer any of their products. 
 
 
 
 
Monitoring 
 
For studies assigned Demography monitoring and enrolling patients via OPEN: 
 
Required submission of patient demographic data for this study will be submitted automatically 
via OPEN.   
 
Note: Serious adverse events must be submitted via CTEP-AERS per protocol guidelines. 
 
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. 
 
Personal information of Study personnel may be transferred outside of the United States by the 
industry funder, EMD Serono, and held or processed by Affiliates of EMD Serono R&D. Affected 
individuals may have rights afforded under the EU – GDPR regulations.  Further information about 
these rights can be obtained by contacting Privacy@emdgroup.com  


S2011 
 
 
Page 59 
Version Date 03/09/2023 
 
 
17.0 
BIBLIOGRAPHY 
 
1  
Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant 
chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder 
cancer. The New England journal of medicine. 2003;349(9):859-66. 
 
2  
Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing 
neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder 
cancer: long-term results of the BA06 30894 trial. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2011;29(16):2171-7. 
 
3  
Advanced Bladder Cancer Meta-analysis C. Neoadjuvant chemotherapy in invasive bladder 
cancer: update of a systematic review and meta-analysis of individual patient data advanced 
bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202-5; discussion 5-6. 
 
4  
Sonpavde G, Goldman BH, Speights VO, Lerner SP, Wood DP, Vogelzang NJ, et al. Quality of 
pathologic response and surgery correlate with survival for patients with completely resected 
bladder cancer after neoadjuvant chemotherapy. Cancer. 2009;115(18):4104-9. 
 
5  
Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G, et al. Impact of renal 
impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial 
carcinoma of the bladder. Cancer. 2006;107(3):506-13. 
 
6  
Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. Treatment of patients 
with 
metastatic 
urothelial 
cancer 
"unfit" 
for 
Cisplatin-based 
chemotherapy. 
J 
Clin 
Oncol.29(17):2432-8. 
 
7  
Hussain SA, Palmer DH, Lloyd B, Collins SI, Barton D, Ansari J, et al. A study of split-dose cisplatin-
based neo-adjuvant chemotherapy in muscle-invasive bladder cancer. Oncol Lett. 2012;3(4):855-
9. 
 
8  
Kim YR, Lee JL, You D, Jeong IG, Song C, Hong B, et al. Gemcitabine plus split-dose cisplatin 
could be a promising alternative to gemcitabine plus carboplatin for cisplatin-unfit patients with 
advanced urothelial carcinoma. Cancer Chemother Pharmacol. 2015;76(1):141-53. 
 
9  
Hussain SA, Stocken DD, Riley P, Palmer DH, Peake DR, Geh JI, et al. A phase I/II study of 
gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients 
with advanced and metastatic bladder cancer. Br J Cancer. 2004;91(5):844-9. 
 
10  
Maughan BL, Agarwal N, Hussain SA, Boucher KM, Von Der Maase H, Kaufman DS, et al. Pooled 
analysis of phase II trials evaluating weekly or conventional cisplatin as first-line therapy for 
advanced urothelial carcinoma. Clin Genitourin Cancer. 2013;11(3):316-20. 
 
11  
De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial 
assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with 
advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. 
J Clin Oncol. 2012;30(2):191-9. 
 
12  
Koie T, Ohyama C, Yamamoto H, Imai A, Hatakeyama S, Yoneyama T, et al. Neoadjuvant 
gemcitabine and carboplatin followed by immediate cystectomy may be associated with a survival 
benefit in patients with clinical T2 bladder cancer. Med Oncol. 2014;31(5):949. 
 
 


S2011 
 
 
Page 60 
Version Date 03/09/2023 
 
 
 
13  
Abdelhafez M WM. SAFETY AND EFFICACY GEMCITABINE-CISPLATIN SPLIT DOSE AS A 
NEOADUVANT CHEMOTHERAPY FOR MUSCLE INVASIVE BLADDER CANCER. AUA annual 
conference April 2017; Volume 197, Issue 4, Supplement, Page e1194. 
 
14  
Koie T, Ohyama C, Yamamoto H, Imai A, Hatakeyama S, Yoneyama T, et al. Neoadjuvant 
gemcitabine and carboplatin followed by immediate cystectomy may be associated with a survival 
benefit in patients with clinical T2 bladder cancer. Med Oncol. 2014;31(5):949. 
 
15  
Murasawa H, Koie T, Ohyama C, Yamamoto H, Imai A, Hatakeyama S, et al. The utility of 
neoadjuvant gemcitabine plus carboplatin followed by immediate radical cystectomy in patients 
with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy. Int J Clin 
Oncol. 2017;22(1):159-65. 
 
16  
Koie T, Ohyama C, Hashimoto Y, Hatakeyama S, Yamamoto H, Yoneyama T, et al. Efficacies and 
safety of neoadjuvant gemcitabine plus carboplatin followed by immediate cystectomy in patients 
with muscle-invasive bladder cancer, including those unfit for cisplatin: a prospective single-arm 
study. Int J Clin Oncol. 2013;18(4):724-30. 
 
17  
Reardon ZD, Patel SG, Zaid HB, Stimson CJ, Resnick MJ, Keegan KA, et al. Trends in the use of 
perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a 
sign of changing tides. Eur Urol. 2015;67(1):165-70. 
 
18  
Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, et al. Adjuvant chemotherapy in 
upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled 
trial. Lancet. 2020;395(10232):1268-77. 
 
19  
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, 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. 2016;387(10031):1909-20. 
 
20  
Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic 
urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 
trial. Lancet Oncol. 2017. 
 
21  
Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and Efficacy of 
Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, 
in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol. 2016;34(26):3119-25. 
 
22  
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as Second-Line 
Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017. 
 
23  
Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, et al. Avelumab in metastatic 
urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two 
expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64. 
 
24  
Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, et al. Randomized phase III 
KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent 
advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019. 
 
25  
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as 
first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial 
carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76. 
 


S2011 
 
 
Page 61 
Version Date 03/09/2023 
 
 
 
 
26  
https://www.prnewswire.com/news-releases/bavencio-significantly-improved-overall-survival-in-
patients-with-locally-advanced-or-metastatic-urothelial-carcinoma-300981078.html. . 
 
27  
Powles T, Park SH, Voog E, Caserta C, Valderrama BP, et al. Avelumab Maintenance Therapy for 
Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230.  
 
28  
Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Luciano R, et al. Pembrolizumab as 
Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial 
Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 
2018:JCO1801148. 
 
29  
Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, et al. Clinical 
efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in 
the ABACUS trial. Nat Med. 2019;25(11):1706-14. 
 
30  
Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Luciano R, et al. Updated Results of PURE-
01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive 
Bladder Carcinoma with Variant Histologies. Eur Urol. 2020;77(4):439-46. 
 
31  
Briganti A, Gandaglia G, Scuderi S, Gallina A, Colombo R, Fossati N, et al. Surgical Safety of 
Radical Cystectomy and Pelvic Lymph Node Dissection Following Neoadjuvant Pembrolizumab in 
Patients with Bladder Cancer: Prospective Assessment of Perioperative Outcomes from the PURE-
01 Trial. Eur Urol. 2020;77(5):576-80. 
 
32 ` 
Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Luciano R, et al. Updated Results of PURE-
01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive 
Bladder Carcinoma with Variant Histologies. Eur Urol. 2020;77(4):439-46. 
 
33  
Necchi A, Raggi D, Gallina A, Ross JS, Fare E, Giannatempo P, et al. Impact of Molecular 
Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant 
Pembrolizumab in Muscle-invasive Bladder Cancer. Eur Urol. 2020. 
 
34  
Necchi A, Bandini M, Calareso G, Raggi D, Pederzoli F, Fare E, et al. Multiparametric Magnetic 
Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant 
Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study. 
Eur Urol. 2020;77(5):636-43. 
 
35  
https://www.gene.com/media/press-releases/14801/2019-08-04/genentechs-tecentriq-
atezolizumab-plus-p. 
 
36  
Grande E, Galsky M, Arranz Arija JA, et al. IMvigor130: efficacy and safety from a Phase 3 study 
of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) 
vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma 
(mUC). Annals of Oncology (2019) 30 (suppl_5): v851-v934 101093/annonc/mdz394. 
 
37  
Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, et al; DANUBE study 
investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in 
previously untreated patients with unresectable, locally advanced or metastatic urothelial 
carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 
Dec;21(12):1574-1588. 
 
 


S2011 
 
 
Page 62 
Version Date 03/09/2023 
 
 
 
38  
Hoimes CJ AC, Hoffman-Censits J, et al A Phase Ib/2 study of neoadjuvant pembrolizumab 
(pembro) and chemotherapy for locally advanced Urothelial Cancer (UC). ESMO 2018 Congress; 
Munich, Germany. 
 
39  
Gupta S, Sonpavde G, Weight CJ, McGregor BA, Gupta S, Maughan BL, et al. Results from 
BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in 
muscle invasive bladder cancer (MIBC) undergoing cystectomy. Journal of Clinical Oncology. 
2020;38(6_suppl):439-. 
 
40  
https://investors.merck.com/news/press-release-details/2019/Mercks-KEYTRUDA-
pembrolizumab-in-Combination-with-Chemotherapy-Met-Primary-Endpoint-of-Pathological-
Complete-Response-pCR-in-Pivotal-Phase-3-KEYNOTE-522-Trial-in-Patients-with-Triple-
Negative-Breast-Cancer-TNBC/default.aspx. 
 
41  
Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Luciano R, et al. Pembrolizumab as 
Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial 
Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 
2018:JCO1801148. 
 
42  
Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, et al. Clinical 
efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in 
the ABACUS trial. Nat Med. 2019;25(11):1706-14. 
 
43  
Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Luciano R, et al. Updated Results of PURE-
01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive 
Bladder Carcinoma with Variant Histologies. Eur Urol. 2020;77(4):439-46. 
 
44  
Briganti A, Gandaglia G, Scuderi S, Gallina A, Colombo R, Fossati N, et al. Surgical Safety of 
Radical Cystectomy and Pelvic Lymph Node Dissection Following Neoadjuvant Pembrolizumab in 
Patients with Bladder Cancer: Prospective Assessment of Perioperative Outcomes from the PURE-
01 Trial. Eur Urol. 2020;77(5):576-80. 
 
45  
Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, et al; IMvigor130 Study Group.Lancet. 
2020 May 16;395(10236):1547-1557.  
 
46  
Grande E, Galsky M, Arranz Arija JA, et al. IMvigor130: efficacy and safety from a Phase 3 study 
of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) 
vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma 
(mUC). Annals of Oncology (2019) 30 (suppl_5): v851-v934 101093/annonc/mdz394. 
 
47  
Hoimes CJ AC, Hoffman-Censits J, et al A Phase Ib/2 study of neoadjuvant pembrolizumab 
(pembro) and chemotherapy for locally advanced Urothelial Cancer (UC). ESMO 2018 Congress; 
Munich, Germany. 
 
48  
Gupta S, Sonpavde G, Weight CJ, McGregor BA, Gupta S, Maughan BL, et al. Results from 
BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in 
muscle invasive bladder cancer (MIBC) undergoing cystectomy. Journal of Clinical Oncology. 
2020;38(6_suppl):439- 
 
49  
Rettig L, Seidenberg S, Parvanova I, Samaras P, Curioni A, Knuth A, et al. Gemcitabine depletes 
regulatory T-cells in human and mice and enhances triggering of vaccine-specific cytotoxic T-cells. 
Int J Cancer. 2011;129(4):832-8. 
 
 


S2011 
 
 
Page 63 
Version Date 03/09/2023 
 
 
 
50  
Homma Y, Taniguchi K, Nakazawa M, Matsuyama R, Mori R, Takeda K, et al. Changes in the 
immune cell population and cell proliferation in peripheral blood after gemcitabine-based 
chemotherapy for pancreatic cancer. Clin Transl Oncol. 2014;16(3):330-5. 
 
 
 
 
51  
Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of Pembrolizumab Plus 
Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast 
Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial. JAMA Oncol. 
2020. 
 
52  
Schmid P, Cortes J, Pusztai L, McArthur H, Kummel S, Bergh J, et al. Pembrolizumab for Early 
Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-21. 
 
53  
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab 
plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-
92. 
 
54  
Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-Line 
Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 
2018;379(23):2220-9. 
 
55  
Sonpavde G, Goldman BH, Speights VO, Lerner SP, Wood DP, Vogelzang NJ, et al. Quality of 
pathologic response and surgery correlate with survival for patients with completely resected 
bladder cancer after neoadjuvant chemotherapy. Cancer. 2009;115(18):4104-9. 
 
56  
Sonpavde G, Khan MM, Lerner SP, Svatek RS, Novara G, Karakiewicz PI, et al. Disease-free 
survival at 2 or 3 years correlates with 5-year overall survival of patients undergoing radical 
cystectomy for muscle invasive bladder cancer. J Urol. 2011;185(2):456-61. 
 
57  
Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Vavassori I, Barni S. Correlation of pathologic complete 
response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: 
a meta-analysis. Eur Urol. 2014;65(2):350-7. 
 
58  
Lim CS, Tirumani S, van der Pol CB, Alessandrino F, Sonpavde GP, Silverman SG, et al. Use of 
Quantitative T2-Weighted and Apparent Diffusion Coefficient Texture Features of Bladder Cancer 
and Extravesical Fat for Local Tumor Staging After Transurethral Resection. AJR Am J Roentgenol. 
2019:1-10. 
 
59  
Alessandrino F, Gujrathi R, Nassar AH, Alzaghal A, Ravi A, McGregor B, et al. Predictive Role of 
Computed Tomography Texture Analysis in Patients with Metastatic Urothelial Cancer Treated with 
Programmed Death-1 and Programmed Death-ligand 1 Inhibitors. Eur Urol Oncol. 2019. 
 
60  
Agarwal N, Pal SK, Hahn AW, Nussenzveig RH, Pond GR, Gupta SV, et al. Characterization of 
metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. 
Cancer. 2018;124(10):2115-24. 
 
61  
Grivaas P, Lalani AA, Pond GR, Nagy RJ, Faltas B, Agarwal N, et al. Circulating Tumor DNA 
Alterations in Advanced Urothelial Carcinoma and Association with Clinical Outcomes: A Pilot 
Study. Eur Urol Oncol. 2019. 
 
 


S2011 
 
 
Page 64 
Version Date 03/09/2023 
 
 
 
 
 
 


S2011 
 
 
Page 65 
Version Date 03/09/2023 
 
 
18.0 
Appendix 
 
18.1 
New York Heart Association Functional Classification  
 
18.2 
Patient Clinical Trial Wallet Card 
 
18.3 
Instructions for Biospecimen Bank 
 
 
 
 


S2011 
 
 
Page 66 
Version Date 03/09/2023 
 
 
 
18.1 
 New York Heart Association Functional Classification  
 
Functional Capacity 
Objective Assessment
Class I. Patients with cardiac disease but without resulting 
limitation of physical activity.  Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea, or anginal 
pain. 
A. No objective evidence of 
cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight 
limitation of physical activity.  They are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III.  Patients with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable at rest.  
Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV.  Patients with cardiac disease resulting in inability 
to carry on physical activity without discomfort.  Symptoms of 
heart failure or the anginal syndrome may be present even at 
rest.  If any physical activity is undertaken, discomfort is 
increased. 
D. Objective evidence of 
severe cardiovascular disease.
 
18.2 
Patient Clinical Trial Wallet Card 
 
 
CLINICAL TRIAL WALLET CARD
Show this card to all of your healthcare providers and keep it 
with you in case you go to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):        
 
 
 
Version mmm/yyyy 
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov
 
 
 
 
 


S2011 
 
 
Page 67 
Version Date 03/09/2023 
 
 
18.3 Instructions for BioSpecimen bank 
 
a. 
Tissue 
 
FFPE unstained slides from pre-study TURBT. The slides will be stored in 
a -20°C freezer after accession and barcoding.  
 
FFPE unstained slides from radical cystectomy, nephroureterectomy, or 
ureterectomy. Upon receipt, the Bank will accession, barcode, and store 
FFPE slides in a -20°C freezer. If a block is received, it will be barcoded 
and stored at room temperature for future sectioning. The block will not be 
returned per SWOG policy unless written request is received. 10 slides will 
be cut before return of the block.  
 
b. 
Blood: 
 
Whole blood in EDTA tube:  Upon receipt, the Bank will isolate plasma and 
bank in 1 ml aliquots, in a -80°C freezer until distribution.  
 
 
Blood in Streck cfDNA tubes:  Buffy coat and plasma are processed from 
blood in Streck cfDNA tubes. Plasma is processed following a double-
centrifugation protocol. Aliquots of plasma are stored in a -80°C freezer. 
 
 
Blood in sodium heparin: Buffy coat is processed from blood in a heparin 
tube and stored in a -80°C freezer. 
 
c. 
Urine 
 
Urine: Upon receipt, the bank will accession, barcode the frozen pellet and 
supernatant aliquots, and store them in a -80°C freezer. 
 
The Bank will retain all specimens until CTEP approves use of the specimens 
for translational medicine studies. 
 
 
 

ICF_001.pdf: 
Readability Statistics: 
S2011 
Flesch Reading Ease:  62.8 
Page 1 
Flesch-Kincaid Grade Level 8.3 
Version Date 03/09/2023 
 
 
 
 
 
Research Study Informed Consent Document 
Study Title for Participants:  Testing the addition of an anti-cancer 
immunotherapy drug, avelumab, to gemcitabine and carboplatin chemotherapy 
prior to surgery in muscle invasive urinary tract cancer vs. surgery alone in patients 
who are not able to receive cisplatin therapy. 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
S2011, “Randomized Phase II Trial of Gemcitabine, Avelumab and Carboplatin 
vs. No Neoadjuvant Therapy Preceding Surgery for Cisplatin-Ineligible Muscle-
Invasive Urothelial Carcinoma: SWOG GAP TRIAL.”  
(NCT# 04871529) 
 
 
 
OVERVIEW AND KEY INFORMATION 
(This section is a summary of the main consent form) 
What am I being asked to do? 
 
We are asking you to take part in a research study. This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services. We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer.  
We are asking you to take part in this research study because you have muscle-invasive urinary 
tract (bladder or upper urinary tract) cancer and cannot receive cisplatin chemotherapy before 
surgery. 
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 


 
S2011 
 
Page 2 
 
Version Date 03/09/2023 
 
 
 
Why is this study being done? 
 
This study is being done to answer the following question:  
 
Can we lower the chance of muscle invasive urinary tract cancer growing or spreading, in people 
who cannot receive cisplatin therapy, by combining a new immunotherapy drug, avelumab, to 
the combination of chemotherapy drugs that can be safely given prior to surgery when compared 
to surgery alone and increase the chance that cancer completely disappears at the time of 
surgery? 
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for muscle-invasive bladder or upper urinary tract cancer.  The usual approach is 
defined as the care most people get for muscle-invasive urinary tract cancer when they cannot 
receive cisplatin therapy due to poor kidney function, poor physical fitness or other medical 
problems.  
What is the usual approach to treating muscle-invasive urothelial cancer? 
 
The usual approach for patients who can not receive cisplatin chemotherapy and are not in a 
study is surgery alone (bladder removal, upper urinary tract removal, or upper urinary tract and 
kidney removal based on the location of the cancer).  Your doctor can explain which treatment 
may be best for you.  For patients who get the usual approach for this cancer, about 50 out of 100 
are free of cancer after 5 years.   
What are my choices if I decide not to take part in this study? 
 
 You may choose to have the usual approach described above. 
 You may choose to take part in a different research study, if one is available. 
 You may choose not to be treated for cancer. 
 You may choose to only get comfort care to help relieve your symptoms and not get 
treated for cancer.   
What will happen if I decide to take part in this study? 
 
If you decide to take part in this study, you will either get the study drugs gemcitabine, 
carboplatin and avelumab for up to 12 weeks before having surgery or you will have surgery 
alone (bladder removal, upper urinary tract removal, or upper urinary tract and kidney removal 
based on the location of the cancer).    
 
After your surgery, your doctor will continue to follow your condition for up to 5 years and 
watch you for side effects.  You will visit the doctor’s office for blood tests and scans every 3 
months for the first 2 years after registration, then twice a year for 1 year, then once a year for 2 
more years.  This means that you will keep seeing your doctor in office for a total of 5 years after 
you are registered to this study.   


 
S2011 
 
Page 3 
 
Version Date 03/09/2023 
 
 
 
What are the risks and benefits of taking part in this study? 
 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that receiving gemcitabine, carboplatin and 
avelumab before having surgery may not be as good as the usual approach for the type of cancer 
you have at shrinking or stopping the cancer from growing.     
 
There is also a risk that you could have side effects from the gemcitabine, carboplatin, and 
avelumab.  These side effects may be worse and may be different than you would get with the 
usual approach for the type of cancer you have.    
 
Some of the most common side effects that the study doctors know about are: 
 Lack of energy 
 Muscle pain 
 Diarrhea 
 Nausea 
 Breathing difficulty 
 Decreased hunger 
 Infections 
 
There may be some risks that the study doctors do not yet know about.   
 
Benefits 
 
There is evidence that having surgery alone is effective in stopping the urothelial cancer from 
growing.  It is not possible to know now if taking gemcitabine, carboplatin and avelumab will 
extend your life compared to the usual approach.  This study will help the study doctors learn 
things that will help people in the future. 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  This may mean slowly stopping the study drugs so that there is not a sudden unsafe 
change, risk to your health, etc.  If you stop, you can decide if you want to keep letting the study 
doctor know how you are doing. 
 


 
S2011 
 
Page 4 
 
Version Date 03/09/2023 
 
 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
 The study is stopped by the National Cancer Institute (NCI), Institutional Review Board 
(IRB), Food and Drug Administration (FDA), or study sponsor (SWOG).  The study 
sponsor is the organization who oversees the study.  
 Your health changes and the study is no longer in your best interest. 
 New information becomes available and the study is no longer in your best interest. 
 You do not follow the study rules. 
 For women: You become pregnant while on the study. 
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
 
 
MAIN SCREENING CONSENT FORM 
 What is the purpose of this study? 
 
The purpose of this study is to compare the usual treatment alone to using gemcitabine, 
carboplatin and avelumab plus the usual treatment.  The addition of gemcitabine, carboplatin, 
and avelumab to the usual treatment could shrink the cancer or prevent it from returning.  But, it 
could also cause side effects, which are described in the risks section below.  
 
This study will help the study doctors find out if this different approach is better, the same, or 
worse than the usual approach.  To decide if it is better, the study doctors will be looking to see if 
gemcitabine, carboplatin and avelumab increases the number of people who do not have 
urothelial cancer at the time of surgery from 15% to 35%. 
 
The chemotherapy drug, avelumab, is already approved by the FDA for use in bladder cancer.  
However, most of the time it is used after bladder removal surgery.  There will be about 196 
people taking part in this study. 
What are the study groups? 
 
This study has 2 study groups. 
 


 
S2011 
 
Page 5 
 
Version Date 03/09/2023 
 
 
 
 Group 1  
 
If you are in this group, you will get the drugs gemcitabine, carboplatin, and avelumab 
for 12 weeks, and then you will get the usual care surgery that is described for Group 2.  
You will get gemcitabine through a vein in your arm over 30 minutes on Days 1, 8, 22, 
29, 43, 50, 61, and 71.  You will get carboplatin through a vein in your arm over 30 
minutes on Days 1, 22, 43, and 64.  You will get avelumab through a vein in your arm 
over 60 minutes on Days 1, 15, 29, 43, 57, and 71. 
 
These drugs are all approved by the FDA for use in patients with the type of cancer you 
have, but they are not approved for use in patients prior to surgery in the way they are 
being used in this study.   
 
There will be about 98 people in this group. 
 
 Group 2 
 
If you are in this group, you will get the usual care surgery.  The surgery could include 
removal of the bladder, removal of the upper urinary tract, or removal of the upper 
urinary tract and kidney, depending on where the cancer is located  
 
There will be about 98 people in this group. 
 
We will use a computer to assign you to one of the study groups.  This process is called 
“randomization.”  It means that your doctor will not choose and you cannot choose which study 
group you are in.  You will be put into a group by chance. You will have an equal chance of 
being in Group 1 or Group 2. 
 
Another way to find out what will happen to you during this study is to read the chart below. 
Start reading at the left side and read across to the right., following the lines and arrows. 
 
 
 
  
Randomize – 
The computer will 
randomly put you in a 
study group. 
Group 2  
(Usual Approach Group) 
surgery alone 
You agree to take 
part in the study 
and sign this 
consent form. 
Group 1  
(Study Group) 
Gemcitabine, Carboplatin 
and Avelumab followed by 
surgery 


 
S2011 
 
Page 6 
 
Version Date 03/09/2023 
 
 
 
What exams, tests, and procedures are involved in this study? 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study. 
 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care.  We will use them to 
carefully follow the effects of the study treatment, including preventing and managing side 
effects.   
 
These exams, tests, and procedures to monitor your safety and health include:   
 
 Blood tests done each week you receive study drug. 
 Thyroid testing done before you begin treatment, about 7 weeks after you start treatment, 
and about 3 months after your surgery. 
 
What risks can I expect from taking part in this study? 
 
General Risks 
 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for the type of cancer you have at preventing the cancer from coming back.   
 
You also may have the following discomforts: 
 
 Spend more time in the hospital or doctor’s office. 
 Be asked sensitive or private questions about things you normally do not discuss. 
 May not be able to take part in future studies.  
 
The study drugs used in this study could be very harmful to an unborn or newborn baby.  There 
may be some risks that doctors do not yet know about.  It is very important that you check with 
your study doctor about what types of birth control or pregnancy prevention to use during the 
study and for 1 month after you have completed the study. 
 
This study will use a sample of your tissue.  Generally, your hospital will keep some of your 
tissue from your surgery.  This tissue may be used to help treat you for cancer in the 
future.  Because this study will need to use some of this tissue, there is a small risk that it could 
be used up. This is only for participants who consent to banking for future research.  This is 
discussed more later in this consent form in the section about optional procedures.       
 
 
 


 
S2011 
 
Page 7 
 
Version Date 03/09/2023 
 
 
 
Side Effect Risks 
 
The drugs and surgery used in this study may affect how different parts of your body work such 
as your liver, kidneys, heart, and blood.  The study doctor will test your blood and let you know 
if changes occur that may affect your health. 
 
There is also a risk that you could have other side effects from the study drugs and surgery.  Here 
are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
 If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
 Your study doctor will work with you to treat your side effects. 
 Your study doctor may adjust the study drugs to try to reduce side effects. 
 
This study is looking at a combination of drugs given before surgery vs. surgery alone, which is 
used to treat this type of cancer.  This different combination of drugs may increase your side 
effects or may cause new side effects.   
 
Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Study Group 1 – Possible side effects of gemcitabine, carboplatin and avelumab are listed in the 
tables below.   
 
 
 


 
S2011 
 
Page 8 
 
Version Date 03/09/2023 
 
 
 
Possible Side Effects of Gemcitabine 
(Table Version Date: October 17, 2019) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Gemcitabine, more than 20 and up to 100 may have: 
 Infection, especially when white blood cell count is low 
 Bruising, bleeding 
 Anemia which may require a blood transfusion 
 Blood in urine 
 Nausea, vomiting 
 Flu-like symptoms of muscle pain, fever, headache, chills and fatigue 
 Muscle weakness 
 Feeling of "pins and needles" in arms and legs 
 Numbness and tingling of the arms and legs 
 Swelling of arms, legs 
 Tiredness 
 Difficulty sleeping 
 Rash 
 Hair loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Gemcitabine, from 4 to 20 may have: 
 Fluid in the organs which may cause low blood pressure, shortness of breath, swelling 
of ankles 
 Scarring of the lungs 
 Shortness of breath 
 Liver damage which may cause yellowing of eyes and skin, swelling 
 Diarrhea, constipation 
 Sores in mouth which may cause difficulty swallowing 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 Swelling and redness of the area of radiation 
 Blisters on the skin 
 
RARE, AND SERIOUS 
In 100 people receiving Gemcitabine, 3 or fewer may have: 
 Brain damage, Posterior Reversible Encephalopathy syndrome, which may cause 
headache, seizure, blindness 
 Blockage of the airway which may cause cough 
 Blood clot 


 
S2011 
 
Page 9 
 
Version Date 03/09/2023 
 
 
 
RARE, AND SERIOUS 
In 100 people receiving Gemcitabine, 3 or fewer may have: 
 Severe blood Infection 
 Anemia, kidney problems which may require dialysis 
 
Possible Side Effects of Carboplatin 
(Table Version Date: October 15, 2020) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, more than 20 and up to 100 may have: 
 Infection, especially when white blood cell count is low 
 Bruising, bleeding 
 Anemia which may cause tiredness, or may require blood transfusions 
 Vomiting, nausea 
 Pain 
 Hair loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, from 4 to 20 may have: 
 Diarrhea, Constipation, belly pain 
 Changes in taste 
 Numbness and tingling in fingers and toes 
 Weakness 
 
RARE, AND SERIOUS 
In 100 people receiving Carboplatin, 3 or fewer may have: 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 Visual loss 
 Difficulty hearing 
 
 
 
 


 
S2011 
 
Page 10 
 
Version Date 03/09/2023 
 
 
 
Possible Side Effects of Avelumab  
(Table Version Date: April 23, 2019) 
Special precautions 
Side effects of avelumab may happen anytime during treatment or even after your treatment 
has ended.  Some of these problems may happen more often when avelumab is used in 
combination with gemcitabine and carboplatin.   Call or see your healthcare provider right 
away if you develop any problems listed below or the symptoms get worse. 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving avelumab, more than 20 and up to 100 may have: 
 Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving avelumab, from 4 to 20 may have: 
 Anemia which may require blood transfusion 
 Diarrhea, nausea, vomiting 
 Chills, fever 
 Flu-like symptoms including body aches 
 Infection 
 Reaction during or following a drug infusion which may cause fever, chills, rash, 
low blood pressure 
 Bruising, bleeding 
 Loss of appetite 
 Cough 
 Dry skin 
 Itching, acne, rash 
 
Avelumab may cause your immune system to attack normal organs and cause side effects 
in many parts of the body. These problems may include but are not limited to: 
 Hormone gland problems (especially the thyroid, pituitary and adrenal glands, 
and pancreas).  Signs and symptoms may include: headaches that will not go away 
or unusual headaches, extreme tiredness or changes in mood or behavior 
decreased sex drive; weight loss or weight gain; excessive thirst or urine; dizziness 
or fainting [the term above is a clinical manifestation of lab values not previously 
listed on the risk list] 
 Damage to the pancreas which may cause belly pain and hospitalization  
 Pain or swelling of the joints 
 Problem of the muscle (myositis), which can cause muscle pain and severe muscle 
weakness sometimes with dark urine 


 
S2011 
 
Page 11 
 
Version Date 03/09/2023 
 
 
 
RARE, AND SERIOUS 
In 100 people receiving avelumab, 3 or fewer may have: 
Avelumab may cause your immune system to attack normal organs and cause side effects 
in many parts of the body. These problems may include but are not limited to: 
 Heart problems including inflammation and heart failure.  Symptoms and signs of 
heart problem may include: Shortness of breath, swelling of the ankle and body 
 Swelling and redness of the eye 
 Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine. 
Signs and symptoms of colitis may include: diarrhea or increase in bowel 
movements, blood in your stools or dark, tarry, sticky stools, severe belly pain or 
tenderness  
 Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of 
hepatitis may include: yellowing of your skin or the whites of your eyes, severe 
nausea or vomiting; drowsiness; pain in the right upper belly 
 A condition with high blood sugar (diabetes) which leads to tiredness, frequent 
urination or excessive thirst which may require treatment with insulin 
 Problem of the nerves that can cause paralysis.  Signs and symptoms may include: 
numbness, tingling of hands and feet; weakness of the arms, legs and facial muscle 
movement 
 Inflammation of the brain (meningitis/encephalitis), which may cause: headache, 
confusion, sleepiness, seizures, and stiff neck 
 Kidney problems, including nephritis and kidney failure requiring dialysis.  Signs 
of kidney problems may include: decrease in the amount of urine, blood in your 
urine, ankle swelling 
 Lung problems (pneumonitis and pleural effusion). Symptoms may include: new 
or worsening cough, chest pain, shortness of breath 
 
 
Additional Drug Risks 
 
The study drug, avelumab, could interact with other drugs.  Your study doctor will give you a 
participant clinical trial wallet card that lists these study drugs.  Share this information with your 
family members, caregivers, other health care providers, and pharmacists. 
 
Rarely, there are problems getting enough supplies of a study drug.  If that happens, your doctor 
will talk with you about your options. 
 
 


 
S2011 
 
Page 12 
 
Version Date 03/09/2023 
 
 
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
 Keep your study appointments. 
 Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  For all:  Tell your study doctor right away if you 
think that you or your partner have become pregnant during the study or within 6 months after 
your last dose of study drug.   
What are the costs of taking part in this study? 
 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for the type of cancer you have.  
This includes: 
 
 the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
 the costs of getting the gemcitabine, carboplatin, and avelumab ready and giving them to 
you. 
 your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You or your insurance provider will not have to pay for exams, tests, and procedures done for 
research purposes only or that are covered by the study.  These include:   
 
 The extra blood tests during each cycle of treatment. 
 The thyroid tests done before study, at about 7 weeks after starting study treatment, and 
at about 3 months after surgery. 
 
You or your insurance provider will not have to pay for the avelumab while you take part in this 
study. 
 


 
S2011 
 
Page 13 
 
Version Date 03/09/2023 
 
 
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat the type of cancer you have.  You may: 
 
 Have more travel costs. 
 Need to take more time off work. 
 Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment. 
 
What happens if I am injured because I took part in this study? 
 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at or receive copies of some of the information in your 
study records.  Your health information in the research database also may be shared with these 
organizations.  They must keep your information private, unless required by law to give it to 
another group.   
 
Some of these organizations are: 
 


 
S2011 
 
Page 14 
 
Version Date 03/09/2023 
 
 
 
 The study sponsor and any company supporting the study drug avelumab now or in the 
future. This would include any organization helping the company with the study.  
 The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study.  
 The FDA and the groups it works with to review research.   
 The NCI and the groups it works with to review research. 
 The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research. 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 
may be stored and shared for future use in public databases.  However, your name and other 
personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
 You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
 You and your study doctor will not be told when or what type of research will be done. 
 You will not get reports or other information about any research that is done using your 
information.  
Where can I get more information?   
 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor _____________________________ 
(*insert name of study doctor[s]*) at__________________________ (*insert telephone number, 
and email address if appropriate*). 
 
For questions about your rights while in this study, call the ______________________  (*insert 
name of organization or center*) Institutional Review Board at_________________________ 
(*insert telephone number*).  
 


 
S2011 
 
Page 15 
 
Version Date 03/09/2023 
 
 
 
 
 
 
ADDITIONAL STUDIES SECTION: 
(This section is about optional studies you can choose to take part in) 
Optional sample collections for known laboratory studies and/or storage for 
possible future studies 
 
Researchers are trying to learn more about cancer and other health problems using blood, urine, 
and tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Unknown future studies 
 
If you choose to take part in this optional study, a sample of tissue from your previous biopsy 
will be collected and stored.  Storing samples for future studies is called “biobanking.”  The 
biobank is being run by SWOG and is supported by the NCI.  This is a publicly funded study. 
Samples from publicly funded studies are required to be shared as broadly as possible. However, 
we will protect your privacy. The goal of this is to make more research possible that may 
improve people’s health.  
 
The biobank is a public research resource. It has controlled access.  This means that researchers 
who want to get samples and data from it must submit a specific research request. The request 
identifies who they are and what their planned research project is. Before getting the samples and 
data, the researchers must agree to keep the data private, only use it for their planned research 
project, and never use it to try to identify you.  
 
Right now, we don’t know what research may be done in the future using your blood, urine and 
tissue samples.  This means that: 
 
 You will not be asked if you agree to take part in the future research studies.   
 You and your study doctor will not be told when or what type of research will be done. 
 You will not get reports or other information about any research that is done using your 
samples.  
 
Unknown future research studies may include sequencing of all or part of your DNA.  This is called 
genomic sequencing.  Sequencing allows researchers to identify your genetic code. Changes in your 
genetic code may just be in your tumor tissue.  These are called somatic changes.  Changes may also be in 


 
S2011 
 
Page 16 
 
Version Date 03/09/2023 
 
 
 
your normal tissue and passed down through your family.  For example, these genetic changes may be 
passed down to your children in the same way that eye and hair color are passed down. These are called 
germline changes.  If only tumor tissue is sequenced, we will not know if a genetic change in your tumor 
is also in your normal tissue.  This is why sometimes both normal tissue and tumor tissue are sequenced.  
This helps researchers understand if a genetic change happened only in the cancer tissue, or in your 
normal tissue as well.   
What is involved in this optional sample collection? 
 
If you agree to take part, here is what will happen next: 
1. About 6 teaspoons of blood will be collected from a vein in your arm at up to 3 times.  A 
sample from the tissue that was collected at the time of the biopsy you had when the 
cancer was first diagnosed will be sent to the biobank.  A sample of tissue will be 
collected from the surgery you have while you are on the study and will be sent to the 
biobank.  A sample of urine will be collected and sent to the biobank at up to 2 times. 
2. Your samples will be stored in the biobank.  There is no limit on the length of time we 
will keep your samples and research information.  The samples will be kept until they are 
used for research or destroyed. 
3. Researchers can only get samples from the biobank after their research has been 
approved by experts.   
4. Some of your genetic and health information may be placed in central databases for 
researchers to use.  The databases will not include your name or contact information.   
 
What are the risks in this optional sample collection? 
 
 The most common risks related to drawing blood from your arm are brief pain and maybe 
a bruise.   
 Generally, hospitals will keep some of your tissue. This tissue may be used to help treat 
you for cancer in the future.  There is a small risk that when this tissue sample is 
submitted to the biobank for this optional sample collection, your tissue could be used up.     
 Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
 In some cases, this information could be used to make it harder for you to get or keep a 
job and get or keep health insurance.   
 
How will information about me be kept private? 
 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 


 
S2011 
 
Page 17 
 
Version Date 03/09/2023 
 
 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the benefits to taking part in this optional sample collection? 
 
You will not benefit from taking part.  
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments to this optional sample collection? 
 
There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
What if I change my mind about this optional sample collection? 
 
If you decide you no longer want your samples to be used, you can call the study doctor, 
__________________ (*insert name of study doctor for main trial*), at_________________ 
(*insert telephone number of study doctor for main trial*), who will let the biobank know.  Then, 
any sample that remains in the biobank will be destroyed or returned to your study doctor.  This 
will not apply to any samples or related health information that have already been given to or 
used by researchers. 
 
What if I have questions about this optional sample collection? 
 
If you have questions about the use of your samples for research, contact the study doctor, 
_____________________________(*insert name of study doctor for main trial*), at 
_________________________(*insert telephone number of study doctor for main trial*). 
 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for unknown future studies: 
 
I agree that my samples and related health information may be kept in a biobank for use in future 
health research. 
 
 
YES 
 
NO 


 
S2011 
 
Page 18 
 
Version Date 03/09/2023 
 
 
 
Contact for Future Research 
 
I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
This is the end of the section about optional studies. 
 
 
My signature agreeing to take part in the study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  I also agree to take part in any additional studies where I circles 
“yes”. 
 
 
Participant’s signature (or legally authorized representative) 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature