A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) With Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer
Phase: PHASE2
Conditions: Bladder Cancer
Sponsor: SWOG Cancer Research Network

 
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PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
SWOG 
TITLE PAGE 
A RANDOMIZED PHASE ii STUDY OF CO-EXPRESSION EXTRAPOLATION (COXEN) with 
NEOADJUVANT CHEMOTHERAPY FOR LOCALIZED, MUSCLE-INVASIVE BLADDER CANCER 
 
NCT #02177695 
 
STUDY CHAIRS: 
AGENTS: 
 
Principal Investigator 
IND-Exempt Agents: 
Thomas W. Flaig, M.D. (Medical Oncology) 
Gemcitabine hydrochloride (NSC-613327) 
University of Colorado, Denver 
Cisplatin (NSC-119875) 
MS C290, 13001 E. 17th Pl., Room E1342  
Methotrexate (NSC-740) 
Aurora, CO 80045 
Vinblastine sulfate (NSC-49842) 
Phone:  303/724-0499 
Doxorubicin (Adriamycin) (NSC-123127) 
FAX:  303/724-3889  
Filgrastim (G-CSF) (NSC-614629) 
E-mail:  thomas.flaig@ucdenver.edu  
Pegfilgrastim (Neulasta) (NSC-725961) 
 
 
 
 
Siamak Daneshmand, M.D. (Urology) 
David J. McConkey, Ph.D. (Translational Medicine) 
University of Southern California 
Johns Hopkins Greenberg Bladder Cancer Institute 
Norris Comprehensive Cancer Center 
Brady Urological Institute at Johns Hopkins 
Institute of Urology 
600 North Wolfe Street, 
1441 Eastlake Avenue, #7416 
Marburg Building / Suite 149 
Los Angeles, CA 90089 
Baltimore, MD 21287-2101 
Phone: 323/865-3700 
Phone: 410/502-4149 
FAX:  323/865-0120 
Fax: 410/614-7526 
E-mail:  daneshma@usc.edu  
Email: djmcconkey@jhmi.edu    
 
 
Seth P. Lerner, M.D. (Urology) 
Dan Theodorescu, M.D., Ph.D. (Translational Medicine) 
Baylor College of Medicine  
University of Colorado Cancer Center 
Scott Department of Urology  
13001 East 17th Place, MS F434 
6620 Main Street, Suite 1325 
Aurora, CO 80045 
1441 Eastlake Avenue 
Phone:  303/724-7135 
Houston, TX 77030 
FAX:  303/724-3162 
Phone:  713/798-6841 
E-mail:  dan.theodorescu@ucdenver.edu  
FAX:  713/798-5553 
 
E-mail:  slerner@bcm.edu  
Amir Goldkorn, M.D. (Translational Medicine) 
 
University of Southern California 
M. Scott Lucia, M.D. (Pathology) 
Norris Comprehensive Cancer Center 
University of Colorado, Denver  
Los Angeles, CA  90089 
12801 East 17th Avenue  
Phone:  323/442-7721 
Pathology/MS 8104 
E-mail: agoldkor@med.usc.edu  
Aurora, CO 80045 
 
Phone:  303/724-3470 
 
FAX:  303/724-1427 
 
E-mail:  scott.lucia@ucdenver.edu  
 
 
 
 

 
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BIOSTATISTICIANS: 
 
 
 
Cathy M. Tangen, Dr.P.H. (Biostatistics) 
 
Melissa Plets, M.S. 
 
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: ctangen@fredhutch.org  
E-mail: mplets@fredhutch.org  
 
PATIENT ADVOCATE: 
 
Rick Bangs 
Phone:  248/377-4290 
E-mail:  chezrick@comcast.net  
 
ALLIANCE CHAMPION: 
 
 
Matthew I. Milowsky, M.D. 
 
University of North Carolina at Chapel Hill 
Lineberger Comprehensive Cancer Center 
E-mail:  matt_milowsky@med.unc.edu  
 
 
PARTICIPANTS 
 
ALLIANCE/ Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
 
NRG/NRG Oncology 
 
SWOG/SWOG 
 
NCIC-CTG/NCIC-CTG Trials Group 
 
 
 
 

 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................................. 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 8 
1.1 
Primary Objective ............................................................................................................................. 8 
1.2 
Secondary Objectives ...................................................................................................................... 8 
2.0 
BACKGROUND ............................................................................................................................... 8 
3.0 
DRUG INFORMATION .................................................................................................................. 21 
3.1 
Gemcitabine hydrochloride (Gemzar®) (NSC-613327) ................................................................. 21 
3.2 
Cisplatin (CDDP) (Platinol®) (NSC-119875) .................................................................................. 23 
3.3 
Methotrexate (NSC-740) ................................................................................................................ 25 
3.4 
Vinblastine sulfate (Velban) (NSC-49842) ..................................................................................... 28 
3.5 
Doxorubicin (Adriamycin) (NSC-123127)....................................................................................... 30 
3.6 
Filgrastim (r-metHuG-CSF) (Neupogen®) (NSC-614629) .............................................................. 31 
3.7 
Pegfilgrastim (Neulasta™) ............................................................................................................. 32 
4.0 
STAGING CRITERIA ..................................................................................................................... 34 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 34 
5.1 
Disease Related Criteria ................................................................................................................ 34 
5.2 
Prior Therapy Criteria ..................................................................................................................... 35 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 35 
5.4 
Specimen Submission Criteria ....................................................................................................... 36 
5.5 
Regulatory Criteria ......................................................................................................................... 37 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 37 
7.0 
TREATMENT PLAN ...................................................................................................................... 37 
7.1 
General Considerations ................................................................................................................. 37 
7.2 
Arm 1:  Gemcitabine + Cisplatin (GC) Treatment .......................................................................... 38 
7.3 
Arm 2: Dose Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin (DDMVAC) Treatment .... 39 
7.4 
Timing of Cystectomy After Chemotherapy ................................................................................... 39 
7.5 
Criteria for Removal from Protocol Treatment ............................................................................... 40 
7.6 
Discontinuation of Treatment ......................................................................................................... 40 
7.7 
Follow-Up Period ............................................................................................................................ 40 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 40 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 40 
8.2 
General Dose Modification Considerations.................................................................................... 40 
8.3 
Chemotherapy Dose Levels ........................................................................................................... 41 
8.4 
Dose Modifications ......................................................................................................................... 42 
8.5 
Dose Modifications Contacts ......................................................................................................... 45 
8.6 
8Adverse Event Reporting ............................................................................................................. 45 
9.0 
STUDY CALENDAR ...................................................................................................................... 46 
9.1 
Arm 1 GC – Study Calendar – 21 day cycles ............................................................................... 46 
9.2 
Arm 2 DDMVAC – Study Calendar – 14 day cycles ..................................................................... 48 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 50 
10.1 
Recurrence criteria ......................................................................................................................... 50 
10.2 
Recurrence-Free Survival .............................................................................................................. 50 
10.3 
Overall Survival .............................................................................................................................. 50 
10.4 
Performance Status ....................................................................................................................... 50 
10.5 
Pathologic Response ..................................................................................................................... 50 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 51 
11.1 
Accrual Goal ................................................................................................................................... 51 
11.2 
Analysis of Primary Endpoint ......................................................................................................... 51 
11.3 
Analysis of Secondary Endpoints .................................................................................................. 52 
11.4 
Data and Safety Monitoring Committee Oversight ........................................................................ 53 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 53 

 
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13.0 
REGISTRATION GUIDELINES ..................................................................................................... 53 
13.1 
Registration Timing ........................................................................................................................ 53 
13.2 
Investigator/Site Registration ......................................................................................................... 54 
13.3 
OPEN Registration Requirements ................................................................................................. 54 
13.4 
Registration Procedures................................................................................................................. 55 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 56 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 56 
14.1 
Data Submission Requirement ...................................................................................................... 56 
14.2 
Master Forms ................................................................................................................................. 56 
14.3 
Data Submission Procedures ........................................................................................................ 56 
14.4 
Data Submission Overview and Timepoints .................................................................................. 57 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 59 
15.1 
Specimens for mandatory correlative studies (submitted to the SWOG Specimen Repository – 
Solid Tissue, Myeloma and Lymphoma Division, Lab #201) are mandatory for the patient. ....... 59 
15.2 
Blood Specimen for upCTC (submitted to the Amir Goldkorn Lab, Lab #181) optional for patient60 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 62 
16.1 
Adverse Event Reporting Requirements........................................................................................ 63 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 66 
18.0 
APPENDIX ..................................................................................................................................... 71 
18,1 
New York Heart Association Classifications .................................................................................. 72 
18.2 
Pathology Verification of Tissue Submission Form ....................................................................... 73 
18.3 
Translational Medicine Studies .................................................................................................. 74 
18.3a  microRNA (miRNA) expression profile ...................................................................................... 75 
18.3b  Ultra Pure Circulating Tumor Cells Using Coxen ..................................................................... 77 
18.3c 
 Cisplatin Germline Pharmacogenomics ................................................................................... 85 
18.3d 
DNA Damage Response Gene Alterations ................................................................................ 89 
18.4 
Circulating Tumor Cell (CTC) Instructions for Blood Sample Processing, Packing and Shipping 96 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
 
For regulatory requirements: 
For patient 
enrollments: 
For study data submission: 
The study protocol and all related 
forms and documents must be 
downloaded from the protocol-
specific Web page of the CTSU 
Member Web site located at 
https://www.ctsu.org.  Sites must 
use the current form version and 
adhere to the instructions and 
submission schedule outlined in 
the protocol. 
 
CTSU sites should follow 
procedures outlined in the protocol 
for Site registration, Patient 
Enrollment, Adverse Event 
Reporting, Data Submission 
(including ancillary studies), and 
Drug Procurement. 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal: 
 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 866-651-
2878 to receive further information 
and support.   
 
Contact the CTSU Regulatory Help 
Desk 
at 
866-651-2878 
for 
regulatory assistance. 
 
Please refer to 
the patient 
enrollment 
section for 
instructions on 
using the OPEN 
system. 
 
Online Data Submission:  This protocol will 
use Medidata Rave® for electronic data 
submission.  Access Rave® using your active 
CTEP-IAM userid and password at the 
following URL: 
 
https://login.imedidata.com/selectlogin  
 
Other Tools and Reports:  Institutions 
participating through the CTSU continue to 
have access to other tools and reports 
available on the SWOG Workbench.  Access 
this by using your active CTEP-IAM userid 
and password at the following URL: 
 
https://crawb.crab.org/TXWB/ctsulogon.aspx  
 
The study protocol and all related forms and documents must be downloaded from the protocol-specific 
Web page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the current 
form version and adhere to the instructions and submission schedule outlined in the protocol. 
 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
888-823-5923 
ctsucontact@westat.com  
 

 
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CONTACT INFORMATION 
 
 
For regulatory requirements: 
For patient 
enrollments: 
For study data submission: 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please review the 
CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website: 
https://www.ctsu.org  
The CTSU Web site is located at https://www.ctsu.org  
 

 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Mandatory submission of viable cancer tissue and other specimens for gene expression profiling and 
COXEN score analysis 
**  Collect and submit residual tumor (if applicable).  Enrollment in S1011 should also be considered.   
 
 
Arm 2 
Dose-dense methotrexate, 
vinblastine, doxorubicin & 
cisplatin 
 
(DDMVAC) 
 
Growth Factor Support Required 
Mandatory specimen 
submission* 
Registration/Randomization 
Patients with newly diagnosed 
Stage cT2-T4a N0 M0 
urothelial carcinoma 
Arm 1 
Gemcitabine + 
Cisplatin  
  
(GC) 
 
Growth Factor Support  
(as appropriate) 
 Cystectomy ** 
Follow-up 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To characterize the relationship of DDMVAC- and GC-specific COXEN scores in terms of 
pT0 rate at cystectomy in patients treated with neoadjuvant chemotherapy.  This will be 
done in two ways: 
• 
By assessing whether the treatment-specific COXEN score is prognostic of pT0 rate 
or ≤ pT1 in this patient population and to assess in a preliminary fashion whether the 
COXEN score is a predictive factor distinguishing between these two chemotherapy 
regimens.  
• 
By evaluating the correlation between the GC- and the DDMVAC-COXEN score. 
 
1.2 
Secondary Objectives 
 
a. 
To assess, in a hypothesis generating fashion, the ability of COXEN to select for 
an individual chemotherapy regimen (GC versus DDMVAC). 
 
b. 
To assess the value of gene expression profiling in predicting overall survival (OS) 
in bladder cancer patients treated with neoadjuvant chemotherapy. 
 
c. 
To assess the difference in pT0 rate between the 21-day GC and 14-day DDMVAC 
arms, regardless of gene expression. 
 
d. 
To assess the safety and tolerability of 21-day GC and 14-day DDMVAC 
chemotherapy when given in the neoadjuvant setting for bladder cancer. 
 
 
2.0 
BACKGROUND 
 
It is estimated that there will be 74,690 new cases and 15,580 deaths from bladder cancer in the 
United States in 2014. (1)  The majority of cases are non-muscle invasive and are treated by 
cystoscopic resection, with or without intravesical medical therapy instilled directly into the bladder.  
For those with muscle-invasive disease, therapy consisting of a radical cystectomy or definitive 
radiation therapy is indicated.  Even with these radical treatments, the mortality from muscle-
invasive bladder cancer remains high.  Despite the survival advantage associated with its use, 
neoadjuvant chemotherapy remains poorly utilized in general medical practice in the United States.  
One explanation for the low utilization of neoadjuvant chemotherapy is the concern that some 
patients with surgically curable disease will be chemotherapy-resistant and may progress during 
treatment with neoadjuvant chemotherapy, being rendered incurable.  This protocol will examine 
the utility of gene expression profiling, and more specifically the coexpression extrapolation 
(COXEN) approach, to predict chemotherapy sensitivity in individual patients undergoing 
neoadjuvant chemotherapy for bladder cancer.   
 
 
Chemotherapy for bladder cancer  
The mainstay of contemporary, cytotoxic chemotherapy for advanced bladder cancer has been 
cisplatin-based combination therapy.  MVAC chemotherapy was designed in the mid 1980’s and 
came into general use in the 1990’s. (2)  When compared to single-agent cisplatin, MVAC was 
associated with improved response rates and survival, although the regimen produced notable 
toxicity, mainly hematologic, gastrointestinal and infectious. (3,4) The doublet of gemcitabine and 
cisplatin was later recognized to also have significant activity against urothelial cancer.  In a 
randomized, Phase III study, 405 subjects with Stage IV transitional cell carcinoma were given 
MVAC versus GC. (5) The response rates between the arms were similar (GC, 49%; MVAC 45%) 
as was the overall and progression-free survival (PFS).  The side effects, especially those related 
to bone marrow suppression (neutropenic fever 1%, GC; 12%, MVAC), were greater in the MVAC 

 
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arm as compared to GC-treated subjects.  The long-term results of this study have been reported 
with a median overall survival (OS) of 14.0 months with GC versus 15.2 months with MVAC 
(p=0.66). (6)  
 
Three versus 4 week GC chemotherapy 
In the Phase III trial of GC versus MVAC, the GC was given on a 28 day schedule, the same 
duration as the traditional MVAC cycle.  In regimens utilizing a 28-day cycle of GC, gemcitabine is 
given on Days 1, 8, and 15, although the Day15 dose is oftentimes delayed or skipped due to bone 
marrow suppression, notably thrombocytopenia.  With this recognition, a 21-day GC regimen, with 
gemcitabine given on Days 1 and 8 only, was investigated.  In one retrospective analysis, 212 
subjects with Stage IV transitional cell carcinoma were treated with either 21- or 28-day GC. (7)  
The response rate between the 2 schedules was similar, with an overall response rate of 59.7% 
with the 3 week and 55.6 % with the 4 week regimen; the complete response rate was 21% in both 
arms.  Treatment compliance was improved with the 21-day schedule; with only 19% requiring 
dose modification in the 21-day arm, versus 62% in the 28-day group, with 47% in the latter required 
to omit Day15 gemcitabine.  The rate of febrile neutropenia in the 21-day arm of this study was less 
than 10%.  A smaller, single arm study of 21-day GC in 27 bladder cancer patients demonstrated 
a strong overall response rate of 48% without any Grade 4 toxicity or treatment-related death. (8)  
In addition, a randomized study of 107 patients with mixed cancer types (predominately lung 
cancer) examined the safety and efficacy of 21- versus 28-day GC.  The 3-week schedule was 
better tolerated, with less Grade 3/4 thrombocytopenia (29.5% versus 5.5%) and less delays or 
dose reductions (51% versus 19%).  Only the lung cancer patients were analyzed for response 
rate, since they represented the majority of the enrolled subjects, and these rates were similar 
between the arms.(9)  In summary, even though the randomized Phase III trial of GC versus MVAC 
used 28-day GC schedule, subsequent studies have reported improved tolerance, dose-density 
and preserved efficacy with 21-day GC.   
 
Dose-dense MVAC (DDMVAC) 
In a parallel fashion, efforts were undertaken to improve the tolerability and dose-density of MVAC.  
Early reports of the use of hematologic growth factor support found that dose escalation of MVAC 
in urothelial carcinoma patients was possible and such an approach was associated with a 
favorable response rate. (10,11) With this emerging information, Sternberg et al pursued a 
randomized Phase III trial of high-dose intensity MVAC with granulocyte colony-stimulating factor 
(G-CSF) versus traditional MVAC in 263 advanced urothelial patients. (12) There was a complete 
response rate (CRR) of 21% and an overall response rate (ORR) of 62% with high-dose MVAC, 
compared to a CRR or 9% and ORR of 50% with standard-dose MVAC; the p value for the CR 
difference was 0.009.  Neutropenic fever was more common with standard-dose MVAC (26% 
versus 10%), although this may be attributed to the disproportionate use of GCSF on the high-dose 
(94%) compared to the standard-dose (19%).  In an updated report, with 7 years of follow-up, 
24.6% were alive in the high-dose, versus 13.2% in the standard-dose MVAC arms. (13) While the 
median survival was similar between the 2 groups (15.1 versus 14.9 months), the overall mortality 
hazard ratio (HR) did favor high-dose MVAC (0.76; 95% CI, 0.58 to 0.99).  Taken together, high-
dose MVAC allows for more dose density, with lower toxicity and improved markers of efficacy. 
 
Neoadjuvant chemotherapy for bladder cancer 
Shortly after the development of active, cisplatin-based chemotherapy combinations for bladder 
cancer, the effectiveness of neoadjuvant chemotherapy was investigated.  In an early Scandinavian 
study (NORDIC 1), 325 subjects with T1G3 or T2-T4aNxM0 bladder cancer were randomized to 2 
cycles of cisplatin and doxorubicin versus no chemotherapy before cystectomy, with all subjects 
receiving a short radiation course. (14)  The 5 year survival was 59% with chemotherapy compared 
to 51% without (p=0.1), although most of the advantage seems restricted to those with more 
advanced, local disease; for those with T3/T4a cancer, there was a 15% advantage with the 
application of chemotherapy.  In a follow-up study (NORDIC 2), 317 subjects with T2-T4aNxM0 
urothelial carcinoma of the bladder were randomized to 3 cycles of cisplatin and methotrexate 
versus no neoadjuvant chemotherapy. (15) The rate of complete pathologic response (pT0) was 
higher in the chemotherapy group (26.4%) compared to the non-chemotherapy group (11.5%) 

 
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(p=0.001), with the pT0 finding in the control arm likely attributable to complete transurethral 
resection of the tumor pre-operatively.  The 5-year overall survival (OS) was improved in absolute 
terms by 7%, from 46% to 53%, with neoadjuvant chemotherapy, although this was not statistically 
significant in this relatively small study.  With these and several other small randomized trials 
available, a meta-analysis of platinum-based neoadjuvant chemotherapy in patients with muscle-
invasive bladder cancer was published in 2003. (16) This work found a significant survival benefit 
with neoadjuvant chemotherapy, yielding a HR of 0.87 (95% CI, 0.78 to 0.98).  A second meta-
analysis on this topic was performed in 2004 and included 8 randomized trials of cisplatin 
combination neoadjuvant therapy, with a pooled HR for OS of 0.87 (95% CI, 0.78 to 0.96). (17)  
This work also noted that a major pathologic response was associated with OS in 4 trials, 
supporting the use of pT0 rates as a marker of survival.   
 
Two randomized studies were launched in the late 1980’s to specifically assess the utility of MVAC 
and CMV chemotherapy in the neoadjuvant bladder cancer setting, as these regimens emerged as 
more effective than single-agent cisplatin.  SWOG 8710 enrolled 317 subjects with T2-T4aN0M0 
bladder cancer, randomizing subjects to 3 cycles of standard-dose (28-day) MVAC versus no 
chemotherapy before cystectomy. (18) The median survival was improved in the experimental arm 
(77 versus 44 months) with a p = 0.06, favoring chemotherapy.  The proportion of subjects with a 
pT0 at the time of surgery was also increased in the MVAC arm, 38% versus 15% (p < 0.001).   In 
an important post hoc analysis of SWOG 8710, the significance of mixed histology (pure urothelial 
carcinoma versus a proportion of urothelial carcinoma) was analyzed. (19) Among those with mixed 
tumors, there was a clear survival advantage (HR 0.46; 95% CI, 0.25 to 0.87), supporting the use 
of neoadjuvant, cisplatin-based chemotherapy in those with a component of squamous or glandular 
differentiation in addition to urothelial carcinoma in their tumor.   
 
A second, European-led neoadjuvant study was larger and enrolled 976 subjects with T2 (Grade 
3), T3-T4a N0M0 urothelial cancer of the bladder in subjects planning for either cystectomy or 
definitive external beam radiation therapy. (20)  Participants were randomized to a 21-day cycle of 
cisplatin-methotrexate-vinblastine (CMV) chemotherapy for 3 cycles versus no chemotherapy.  For 
the 417 subjects undergoing cystectomy, the pathologic response rate (pT0 at the time of surgery) 
was 32.5% with chemotherapy versus 12.3% without.  An update of the survival results was 
subsequently published with 8 years of follow-up. (21)  Combining both the radiation and surgery 
groups, neoadjuvant chemotherapy was associated with a 16% reduction in the risk of death (HR, 
0.84; 95% CI, 0.72 to 0.99) and an improvement in the 10-year survival from 30% to 36%.  
Considering the surgical cystectomy subjects alone, the reduction in the risk of death was 26% 
(HR, 0.74; 95% CI, 0.57 to 0.96; p = 0.022).   
 
Neoadjuvant GC chemotherapy  
As noted, since the initiation of these Phase III neoadjuvant studies of MVAC and CMV 
chemotherapy, GC has become a standard approach in advanced urothelial carcinoma, frequently 
favored over the more toxic MVAC regimen.  There is a limited amount of clinical data for the use 
of GC in the neoadjuvant setting.  In one report from investigators at Memorial Sloan-Kettering, the 
results of 42 bladder cancer patients given 21-day neoadjuvant GC was reported and compared 
historical controls given MVAC. (22) The pT0 proportion was 26% with GC, compared to 28% with 
the historical MVAC group.  They also assessed <pT2 rate, which was 36% with GC, versus 35% 
with MVAC.   
 
The prognostic importance of the pathologic T staging 
pT0 at the time of radical cystectomy is associated with long-term and survival outcomes in bladder 
cancer patients.   In the SWOG 8710 trial, regardless of treatment arm, the finding of pT0 at the 
time of surgery correlated with survival. (23) In a subsequent analysis, the impact of pT0 versus 
<pT2 (pT0, pTa, pTis, and pT1) on survival was analyzed.  In the chemotherapy arm, pathologic 
findings of < pT2 was observed in 44%, with 30% having pT0.  The pT0 rate is lower in this analysis 
compared to the original New England Journal of Medicine publication, as patients who did not 
actually receive any chemotherapy were also included.  Those with pT0 had a median OS of 13.6 
years, those with pT1/pTis/pTa had a median OS of 10.6 years, while those with pT2 or great 

 
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disease at surgery had a median OS of just 3.7 years. (24) The impact of pathologic stage on long-
term outcomes was also evaluated in 2230 patients with radical cystectomy, but no adjuvant 
chemotherapy. They found 5.1% had pT0 at the time of surgery; with a median follow-up of 48 
months, 10.1% of these pT0 patients had recurrent disease.  Of note, the recurrence-free outcomes 
were similar between the pT0 and pTa/pTis patients (p = 0.557).  Taken together, these data 
suggest the prognostic significance of both pT0 and <pT2 at the time of cystectomy.   
 
Low utilization of neoadjuvant chemotherapy for bladder cancer 
Despite the supportive data for neoadjuvant chemotherapy in large, Phase III studies, the 
integration of pre-operative chemotherapy for bladder cancer into routine management of bladder 
cancer patients remains stubbornly low.  While there are two randomized Phase III studies with 
positive findings for the use of neoadjuvant chemotherapy with bladder carcinoma, there is no high-
level data supporting adjuvant chemotherapy.  An analysis of newly diagnosed bladder cancer 
patients, as capture in the National Cancer Data Base, examined the use of perioperative 
chemotherapy. (25)  During the period from 1998-2003, the rate of perioperative chemotherapy 
use in Stage III (T3N0M0) patients was 11.6%, with only 1.2% receiving neoadjuvant 
chemotherapy.  This showed that while perioperative chemotherapy was uncommon in general, 
when it was administered, it was almost exclusively in the adjuvant/post-operative setting.  A more 
recent analysis of 2287 patients treated with cystectomy in Canada from 1998-2008, shows a 
similar trend. (26) The overall application of perioperative chemotherapy was low, with only 3.1% 
of pre-operative and 19.4% of post-operative patients receiving such therapy.  A similar trend of 
low neoadjuvant chemotherapy use in eligible bladder cancer patients has been reported in 
modern, US single-institutional studies. (27)  
 
Predictive biomarkers of chemotherapy for bladder cancer 
There are many recent examples of the use of predictive biomarkers for the selection of therapy in 
cancer patients across several different cancer types.  In breast cancer, it has been established 
that response to trastuzumab is largely limited to those with HER2/neu overexpression and specific 
national guidelines detail the testing procedure for HER2/neu assessment to determine the 
appropriateness of trastuzumab therapy. (28,29,30) Other examples of predictive biomarkers in 
oncology include epidermal growth factor receptor mutation in non-small cell lung cancer for 
gefitinib/erlotinib and the presence of the ALK fusion oncogene for the use of crizotinib. 
(31,32,33,34) Notably, these successes involve biologic agents against specific targets, allowing 
for the rational identification and validation of a predictive marker.  While targeted agents have 
been integrated into the general oncology care of many cancer patients, there is currently no proven 
or widely accepted use of molecularly targeted agents in bladder cancer. 
 
The development of predictive markers for cytotoxic agents has been less successful than for the 
newer targeted agents.   One recent Phase III study assessed the usefulness of p53 assessment 
in the adjuvant bladder cancer setting. (35) Past work had suggested both a prognostic and 
predictive role for p53 in bladder cancer. (36) To test this prospectively, patients with pT1-pT2 N0 
M0 disease at the time of cystectomy were tested for p53 expression by immunohistochemistry.  
Those with positive expression were randomized to receive 3 cycles of MVAC versus observation, 
and all p53 negative subjects were observed without additional chemotherapy prescribed.  The 5-
year recurrence rate was approximately 20% regardless of p53 status, failing to show a prognostic 
value of p53 in this setting.  Additionally, there was no difference in the recurrence rate of p53-
positive patients randomized to chemotherapy versus observation, and a predictive role for p53 in 
selecting cisplatin-sensitive bladder cancer patients was not supported. 
 
With the importance of cisplatin therapy in bladder cancer, much of the predictive biomarker 
discovery effort in bladder cancer has focused on markers of platinum sensitivity.  The excision 
repair cross complementing 1 (ERCC1) gene acts in a DNA repair capacity and specifically plays 
a role in the repair of nucleotide excision – a key mechanism of cisplatin activity. (37) In an early 
assessment of the significance of ERCC1’s expression in chemotherapy-treated metastatic bladder 
cancer, Bellmunt et al assessed mRNA levels of ERCC1 in 57 advanced bladder cancer patients 
treated with cisplatin-based combination chemotherapy. (38) Notably, the median OS was 

 
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significantly higher in those with lower ERCC1 levels (25.4 versus 15.4 months) and ERCC1 was 
an independent predictor of survival.  However, there were no significant differences in 
chemotherapy response rates, based on ERCC1 levels, and it was not possible to distinguish this 
as a predictive versus prognostic factor.  In a retrospective analysis of 108 subjects from the AUO-
AB 05/95 adjuvant bladder cancer study treated with cisplatin-combination chemotherapy, ERCC1 
expression levels (by RT-PCR) were assessed and correlated with long-term outcomes. (39) Low 
ERCC1 levels (less than the 75th percentile) were associated with an improved progression-free 
survival (PFS) (HR 0.52; 95% CI, 0.27 to 1.01).  Using Cox regression analysis, there was a 
significant association between ERRC1 levels and PFS (p=0.01).  Despite an improvement in the 
median OS in those with low ERCC1 expression (72.4 versus 33.1 months), this did not reach 
statistical significance (p = 0.19), although this was a relatively small sample size, without 
substantial power to detect small to moderate differences.  Similar findings of a PFS benefit were 
reported in a second study in which the immunohistochemistry expression of ERCC1 was 
retrospectively assessed in 89 patients with advanced urothelial carcinoma treated with cisplatin-
based chemotherapy.(40) There was not a statistical difference in the overall response rate 
(p=0.61) or the OS between the low and high-ERCC1 expression groups of this study; however, 
the PFS was 2.2 months longer in the ERCC1-negative patients and this reach statistical 
significance.  A small study of 22 muscle-invasive bladder cancer patients treated with radiation 
and cisplatin-based chemotherapy assessed clinical response in relation to ERCC1 
immunoreactivity scores. (41)  For those with negative ERCC1 reactivity, the complete response 
rate was 86% compared to 25% in those with positive ERCC1 expression. Not all studies have 
demonstrated a survival or progression advantage with lower ERCC1 levels in cisplatin-treated 
bladder cancer patients.  Matsumura et al assessed ERCC1 via immunostaining in 40 metastatic 
urothelial carcinoma patients treated with GC, but there was no statistically significant difference, 
although the median OS was 13.6 versus 17.1 months in the high and low expression groups, 
respectively. (42)  
 
Other markers have been assessed to predict chemotherapy sensitivity in bladder cancer.  Notably, 
the breast cancer susceptibility gene 1 (BRCA1), an important actor in DNA repair, was assessed 
in the neoadjuvant bladder cancer setting. (43)  The pretreatment samples of 57 patients 
undergoing CMV or GC neoadjuvant chemotherapy were assessed for mRNA expression levels of 
BRCA1.  In those with low BRCA1 levels, the pathologic down-staging (< pT2) rate was 66% versus 
22% in those with high expression (p=0.01).  Additionally, the median OS was 168 months in the 
low/intermediate versus 34 months in the high-expression group (p=0.002).  Of note, Bellmunt et 
al had examined BRCA1 mRNA levels in their evaluation of 57 advanced cancer patients and found 
no correlation with survival or chemotherapy response. (44) The multi-drug resistance gene, 
MDR1, was also assessed by reverse transcription polymerase chain reaction (RT-PCR) in the 
AUO-AB 05/95 adjuvant bladder cohort.  MDR1 expression below the 75% percentile was 
associated with improved OS (HR 0.25; 95% CI, 0.11 to 0.55).  (45) 
 
While ERCC1 has been directly associated with cellular response mechanism related to repairing 
the DNA adducts caused by cisplatin, the mechanism of action of other chemotherapy agents is 
different and may have separate markers of response.  Gemcitabine requires specific plasma 
membrane transporters in order to enter the cells and exert its anti-cancer effect.  One of the main 
transporters in this regard is human equilibrate nucleoside transporter 1 (hENT1) and its 
immunohistochemistry expression has been associated with prolonged survival in patients with 
advanced pancreatic adenocarcinoma treated with gemcitabine. (46,47) A recent investigation 
assessed the hENT1 expression by immunostaining in 40 metastatic bladder cancer patients 
treated with GC chemotherapy. (48) The median OS was longer in patients with high hENT1 
expression compared to low hENT1 expression (17.3 versus 11.6 months, p=0.003) 
 
COXEN – CO-eXpression ExtrapolatioN  
The NCI-60 is an intensively studied group of sixty cell lines from nine common cancer types, which 
provides a rich dataset for evaluating gene expression profiling of drug sensitivity.  These sixty cell 
lines have been treated with tens of thousands of compounds for which the response data is 
publically available. (49) COXEN represents a “correlation of correlations”, allowing for the 

 
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customization of the in silica NCI-60 results and the application of these findings to specific cells or 
patients. (50) The first step in this process is the identification of the gene expression associated 
with individual drug sensitivity in the NCI-60, which was used for the Gene Expression Model (GEM) 
development for the single drug COXEN scores.  These genes are then compared with the 
application set (cellular or human samples), identifying concordant expressing genes.  Therefore, 
only those genes which are relevant to one’s planned application (e.g. present in both the 
application set and the NCI-60 set) are included in the final gene expression profile.  By comparing 
the NCI-60 results with the gene expression of the target findings, a correlation coefficient (COXEN 
coefficient) is derived.  In a phrase, COXEN translates the NCI-60 drug sensitivity data to any other 
cellular or clinical gene expression data set.  This general use of predictive gene expression 
profiling has been employed in other cancer types, such as breast cancer.  In that setting, the 
application of a 21-gene signature to estrogen receptor-positive women being treated with 
tamoxifen adjuvantly, allows for the predication of the likelihood of cancer recurrence. (51)  
 
The COXEN algorithm may be divided into 6 distinct steps (52):  
1. Step 1:  Experimentally determine the drug’s pattern of activity in cells of set 1. 
• 
Step 2:  Experimentally measure molecular characteristics of the cells in set 1. 
• 
Step 3:  Select a subset of those molecular characteristics that most accurately predicts the 
drug’s activity in cell set 1 (‘‘chemosensitivity signature’’ selection). 
• 
Step 4:  Experimentally measure the same molecular characteristics of the cells in set 2. 
• 
Step 5:  Among the molecular characteristics selected in step 3, identify a subset that shows a 
strong pattern of coexpression extrapolation between cell sets 1 and 2. 
• 
Step 6:  Use a multivariate algorithm to predict the drug’s activity in set 2 cells on the basis of 
the drug’s activity pattern in set 1 and the molecular characteristics of set 2 selected in step 5.  
The output of the multivariate analysis is a COXEN score. 
 
COXEN therefore fundamentally differs from the more standard, a posteriori approach to biomarker 
discovery in the search for predictive biomarkers.  In the traditional approach, the baseline tissue 
is profiled, the clinical trial subjects are assessed for treatment response, and this is followed by 
supervised biomarker discovery using these data.  The main disadvantage to this approach is that 
it is not a priori and requires the completion of a clinical trial to generate the gene expression profile. 
It also does not easily allow for the evaluation of drugs with a low overall response rate, even if a 
small subset will respond.  COXEN allows for the immediate validation of the gene expression 
profile in human trials, since the signature is derived in the preclinical arena.  Additionally, COXEN 
has the advantage of identifying new drug candidates with an accompanying predictive biomarker 
(e.g. gene expression profile), providing a means of screening patients to enrich for a responding 
population. (53) COXEN may also shed light on previously unknown mechanisms of drugs actions, 
based on the genes identified as part of the algorithm. (54)  
 
For the COXEN development of the GC and MVAC regimens in bladder cancer, the described 
approach was followed.  The NCI-60, BLA-40, or GDSC-648 cell panels were used in the initial 
discovery of predictive biomarkers for drug sensitivity. These biomarkers were then filtered based 
on their co-expression with a human bladder tumor cohort. (55)  Single drug GEMs were developed 
by means of principal component regression analysis on the NCI60 panel and finalized via 
univariate COX proportional hazard regression on two human bladder cancer cohorts.  The 
Lehmann-treated cohort utilized MVEC and was used for the GEM evaluation and final selection.  
The MVAC-treated Laval cohort (Laval 54) was used for independent validation for methotrexate, 
vinblastine and adriamycin.  For Cisplatin, the entire Laval cohort of 90 was used for independent 
validation, since all received cisplatin.  In contrast, since gemcitabine was not used in the Lehmann 
cohort, the GEM evaluation and final selection utilized the GC-treated Laval cohort (Laval 36) with 
independent validation on the BL40 panel.  (56)   
 
 
 

 
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Single drug COXEN scores (Si) can be calculated by solving the linear regression model: 
 
𝑆𝑆𝑖𝑖=  𝛼𝛼+ ෍𝛽𝛽𝑘𝑘𝑋𝑋𝑘𝑘𝑘𝑘
𝐾𝐾
𝑘𝑘=1
 
 
Which is to be interpreted as the single drug score (Si) = model intercept (α) + summation of probe 
gene expression data (Xki) multiplied by corresponding coefficients (βk).   
 
The COXEN score for combination drugs is a probability score based on 5-year survival and is 
derived from a parametric survival regression model of Single Drug COXEN scores. Let Mi, Vi, Ai, 
Ci, and Gi denote the percentile of COXEN drug response prediction score of i-th patient for each 
Methotrexate, Vinblastine, Adriamycin, Cisplatin, and Gemcitabine, respectively. Then the COXEN 
scores PMVAC and PGC of i-th patient for MVAC and GC are calculated as below. 
 
PMVAC = 𝑒𝑒 –(5𝜆𝜆𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀)1.091486
 
PGC = 𝑒𝑒 –(5𝜆𝜆𝐺𝐺𝐺𝐺)0.8961938
 
Where 
λ𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀= 𝑒𝑒−(0.761211+(0.766369×𝑀𝑀𝑖𝑖)+(0.3657074×𝑉𝑉𝑖𝑖)+(0.7634502×𝐴𝐴𝑖𝑖)+(0.8308788×𝐶𝐶𝑖𝑖)) 
λ𝐺𝐺𝐺𝐺= 𝑒𝑒−(−0.2456275+(2.8852677×𝐺𝐺𝑖𝑖)+(1.6766004×𝐶𝐶𝑖𝑖)). 
 
Model training and evaluation for the combination COXEN models were done via parametric 
survival regression, ROC, and survival analysis on the Lehmann-188 for the MVAC model and 36 
GC treated patients of the Laval-90 for the GC model.  The MVAC model was independently 
validated on the 54 MVAC-treated patients of the Laval-90 cohort (Figure 1).  A quality control 
procedure is in place to determine if any samples need to be discarded for technical or quality 
concerns (Table 1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1.  Quality Control Analysis Steps for Individual MicroArrays Data Sets 
1. Inspect array images 
– 
Examine for “spatial artifacts” (gross problems)  
2. Assess a boxplot and histogram plot of log2 (PM) values for each array 
– 
Looking for consistency across arrays, identifying outliers 
3. Proportion present plot analysis 
– 
Use probe pairs (PM,MM) to test whether gene is “Present” of “Absent” 
– 
Examine for consistency across arrays, identifying outliers 
4. Plot of Hybrid Controls 
– 
Assess that bioB, bioC, bioD, and cre are present in increasing concentrations 
on each array 
5. QC stats plot 
– 
The “qc” function returns an object containing scale-factors,% present, average 
background intensities (values greater than 100 indicates problem) and bioB, 
bioC, bioD, and creX present calls.  It also plots the 3’/5’ ratios of actin and 
GAPDH (3-fold or greater discrepancies between arrays indicates an outlier) 
6. RNA Degradation plot 
– 
It is expected that 5’ end will have more degradation than 3’ end.  Arrays will 
be examined for consistency, identifying outliers 
 
*If a sample is found to have an outlier in more than 2 of these tests, the sample should 
be discarded. 

 
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S1314 
 
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responders was 81% versus 33% in the predicted non-responders (p = 0.002), as shown in Figure 
4B.  Importantly, the COXEN-derived GEP predictions in this cohort were independent of tumor 
stage, grade, sex and gender (Spearman correlation was -0.14 to 0.07). 
 
Takata et al defined a 15 gene signature, derived in a traditional posteriori approach using a training 
and validation set, to predict for tumor down-staging with neoadjuvant MVAC. To test the 
robustness of the Takata gene expression profile versus the COXEN gene expression profile for 
MVAC in this setting, both were applied to the Als et al independent data set.  While the COXEN 
gene expression profile did separate these patients with respect to OS in a statistically significant 
manner, the Takata gene expression profile did not, with a p-value of 0.73. (62)  Combining the 
results of the 2 bladder cancer studies (Als and Takata) and using combination COXEN-derived 
gene expression profile for MVAC, with respect to “responders”, the gene expression profile had a 
sensitivity of 83% and specificity of 64% with a positive predictive value of 71% and a negative 
predictive value of 78%. (63)  In considering this published data, it is noted that the application of 
COXEN in this protocol will use a different predictor than used in these studies, converting to a 
one-at-a-time predictor, to avoid over fitting.  Along with this, we will note that the data from Als et 
al and Taketa et al have the potential to be optimistically biased based on the risk of over fitting 
and re-substitution. 
 
It is recognized that both 
MVAC and GC incorporate 
cisplatin, the most active agent 
against bladder cancer.  As 
shown in Figure 1, despite the 
commonality of cisplatin in both 
regimens, the COXEN GEMs 
for GC and MVAC are distinct 
due to the activity of the other 
agents 
involved 
in 
each 
regimen.  To assess the overall 
effectiveness and specificity of 
the COXEN GEMs relative to 
each regimen, the MVAC and 
GC COXEN GEMs were both 
applied to GC and to MVAC-
treated patients from the Laval 
cohort.  As shown in Figure 5, 
in 
MVAC-treated 
patients 
(n=54), the MVAC COXEN 
GEM (p=0.0019), but not the 
GC COXEN GEM effectively 
segregated patient outcomes. 
The distribution of the 5 year 
survival of the combined Laval 
and Lehman cohorts is show in 
Figure 6. Additionally, a plot of 
MVAC versus GC COXEN 
scores performed separately 
for 
both 
the 
Laval 
and 
Lehmann cohorts demonstrate 
that the scores do not provide 
identical information, despite 
the commonality of cisplatin in 
each regimen (Figure 7). 
 

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Rationale 
Despite positive findings in two Phase III studies in support of cisplatin-based, neoadjuvant 
chemotherapy, the generalize use of such therapy is very low.  While these studies demonstrate a 
survival benefit, it is also clear that some patients are not responsive to chemotherapy.  Therefore, 
it is possible that a chemotherapy-resistant patient may progress to an advanced, unresectable 
state during neoadjuvant chemotherapy.  Such a concern is undoubtedly a factor in the low 
adoption rate of neoadjuvant chemotherapy for bladder cancer.  There are also different 
chemotherapy agents that may be combined with cisplatin including gemcitabine, methotrexate 
and doxorubicin.  There is currently no accepted method to select the optimal secondary 
chemotherapy agent(s) to use in a specific patient, in order to maximize the chances of a response, 
acknowledging that some patients may have a particularly methotrexate-sensitive tumor and would 
be better served by MVAC rather than GC chemotherapy.   
 
COXEN gene expression profile predicts an individual patient’s likelihood of responding to a 
specific chemotherapy agent or combination of chemotherapy agents.  As detailed here, COXEN 
gene expression profiles have been applied to hundreds of patients, including bladder cancer 
patients, with strong predictive characteristics.  This study will begin by randomizing subjects with 
localized, muscle-invasive bladder cancer to either GC or DDMVAC chemotherapy.  Gene 
expression, microRNA expression and tissue microarray samples will be collected prior to 
chemotherapy.  Along with the assessment of other biomarkers, the ability of COXEN to correctly 
predict response, as assess via the pT0 rate, will be tested.  In a follow up study, this collected data 
will serve as the control for a COXEN directed application of neoadjuvant chemotherapy, assessing 
for an increased response rate with this approach. 
 
The ability to predict chemotherapy response would allow a more rational application of 
neoadjuvant chemotherapy.  First, those not sensitive to any standard chemotherapy agents could 
proceed directly to surgery, avoiding potentially detrimental delays and toxicity from predicted 
ineffective chemotherapy.  Second, for those found sensitive to chemotherapy, COXEN could direct 
them to the chemotherapy combination most likely to yield a response, such as GC rather than 
DDMVAC in someone with a predicted response to gemcitabine. 
 
Inclusion of Women and Minorities: 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects. The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below. Both men and women of all races and ethnic groups are eligible for 
this study. 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
3 
18 
21 
Not Hispanic or Latino 
41 
168 
209 
Total Ethnic 
44 
186 
230 
Racial Category 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
0 
2 
2 
Black or African American 
2 
9 
11 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
42 
173 
215 
Racial Category: Total of all Subjects 
44 
186 
230 
 
 
 

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S1314 
 
Page 34 
 
Version Date: 7/15/19 
 
 
 
4.0 
STAGING CRITERIA 
 
AJCC Seventh Edition, 2010 
Patients will be staged according to standard of care methods.  All patients will undergo cystoscopy 
with transurethral resection of the tumor, adequate for staging as muscle-invasive.  Consistent with 
World Health Organization/International Society of Urologic Pathology (WHO/ISUP) – tumors will 
be classified as either low or high-grade. 
 
Clinical Stage 
Primary Tumor (T) 
 
T2   
Tumor invades muscularis propria 
T3   
Tumor invades perivesical tissue 
T4a   
Tumor invades prostatic stroma, uterus, vagina 
 
Regional Lymph Nodes (N) 
 
Regional lymph nodes include both primary and secondary drainage regions.  All other nodes 
above the aortic bifurcation are considered distant lymph nodes. 
 
N0   
No lymph node metastasis 
 
Distant Metastasis (M) 
 
M0  
No distant metastasis 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S1314 Onstudy Form and submit via Medidata 
Rave® (see Section 14.0).  Any potential eligibility issues should be addressed to the SWOG Statistics and 
Data Management Center in Seattle at guquestion@crab.org or 206/652-2267 prior to registration. 
  
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 28 or 56 falls on a weekend 
or holiday, the limit may be extended to the next working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have histologically proven urothelial carcinoma of the bladder.  
Those with mixed histology, including a component of urothelial carcinoma, are 
eligible.  Small cell carcinoma, pure adenocarcinoma, and pure squamous cell 
carcinoma are excluded.   
 
Related to the section outlining disease measurement - the last sentence of that 
section should be as follows).  All disease must be assessed and documented on 
the Baseline Tumor Assessment Form. 
 
b. 
Patients must have Stage cT2-T4a N0 M0 disease.  Clinical T stage is based on 
the TURBT sample and imaging studies. Patients must undergo cystoscopy and 
TURBT as part of the staging procedure (detailed in Section 4.0) within 56 days 
prior to registration.  To exclude non-bulky/low-risk tumors and ensure adequate 

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S1314 
 
Page 36 
 
Version Date: 7/15/19 
 
 
 
f. 
Patients must have adequate hematologic function as evidenced by absolute 
neutrophil count (ANC) ≥ 1,500/mcL, hemoglobin ≥ 9 g/dL, and platelets ≥ 
100,000/mcL. These results must be obtained within 28 days prior to registration. 
 
g. 
Patients must not be known to have hypersensitivity to cisplatin, gemcitabine, 
doxorubicin, vinblastine, methotrexate or filgrastim/pegfilgrastim.   
 
h. 
Patients must not have any incidence of or uncontrolled medical illness (e.g. active 
cardiac symptoms, active systemic infection, etc.) that would limit the patient’s 
ability to participate in the protocol. 
 
i. 
Prestudy history and physical must be obtained within 28 days prior to registration. 
 
j. 
Patients must not be pregnant or nursing due to the potential teratogenic side 
effects of the protocol treatment.  Women/men of reproductive potential must 
agree to use an effective contraceptive method during and for 6 months after 
completing protocol treatment.  A negative pregnancy test (either serum or urine) 
is required within 7 days prior to registration. 
 
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 patient 
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. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 
Stage I or II cancer from which the patient is currently in complete remission, or 
any other cancer from which the patient has been disease free for five years. 
Patients with localized prostate cancer who are being followed by an active 
surveillance program are also eligible.   
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must have tumor tissue from transurethral resection of the bladder tumor 
(TURBT) available for submission for COXEN testing and must agree to 
submission of 20 (10 micron) slides of formal-fixed paraffin embedded (FFPE) 
tissue, with 2 (5 micron) slides at the start and end of the 20 slides, for a total of 
22 unstained slides.  The diagnostic TURBT sample must have been obtained 
within 56 days prior to registration.  All sections should be placed on "plus" slides, 
as is the standard procedure in most pathology units. 
 
b. 
Patients must consent, if residual tumor is present at the time of cystectomy, to the 
submission of 20 (10 micron) unstained slides with 2 (5 micron) slides at the start 
and stop of the series (total of 22 unstained slides). 
 
c. 
Patients must consent to have voided urine (40-50 mL) submitted prior to initiating 
chemotherapy (pre-treatment) and after chemotherapy prior to surgery (post-
treatment). 
 
d. 
Patients must consent to whole blood (2 x 10 mL) submitted prior to initiating 
chemotherapy. 

 
S1314 
 
Page 37 
 
Version Date: 7/15/19 
 
 
 
e. 
Patients must agree to participate in the translational medicine studies outlined in 
Section 18.3. 
 
f. 
Patients must be offered the opportunity to participate in the ultra pure Circulating 
Tumor Cells (upCTCs) study. 
 
5.5 
Regulatory Criteria 
 
a. 
Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed consent 
prior to any study-related procedures in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.4 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 
 
Patients will be randomized using a dynamic balancing algorithm with stratification based on (57): 
 
a. 
Clinical stage:  T2 vs. T3 or T4a.  NOTE: Clinical stage is based on TURBT(s),  bimanual 
exam, and imaging (see Section 5.1b) 
 
b. 
Performance status:  0 vs. 1 
 
 
7.0 
TREATMENT PLAN 
 
For 
treatment 
questions, 
please 
contact 
Dr. 
Thomas 
W. 
Flaig 
at 
303/724-0499 
(S1314question@swog.org)) 
or 
Dr. 
Siamak 
Daneshmand 
at 
323/865-3700 
(S1314question@swog.org).  For dosing principles or questions, please consult the SWOG Policy 
#38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org (then click on "Policies and 
Manuals" under the "Visitors" menu and choose Policy 38). 
 
7.1 
General Considerations 
 
a. 
Subject will be randomized to either Arm 1 (GC) or Arm 2 (DDMVAC) 
 
b. 
Subjects randomized to DDMVAC will have a standard of care assessment of their 
cardiac ejection fraction (via ultrasound or nuclear medicine MUGA assessment) 
to ensure adequate cardiac function before receiving doxorubicin (according to 
institutional standards).  A cardiac ejection fraction assessment within the last 12 
months is acceptable as long as there is no clinical change or new cardiac 
concerns. 
 
c. 
Due to the risk of methotrexate accumulation, subjects randomized to DDMVAC 
must have any moderate to large pleural effusion or ascites drained prior to starting 
chemotherapy.   
 
d. 
Patients are allowed to participate in this study, followed by S1011 (A Phase III 
Surgical Trial to Evaluate the Benefit of a Standard Versus an Extended Pelvic 
Lymphadenectomy Performed At Time of Radial Cystectomy For Muscle Invasive 
Urothelial Cancer) as long as all the eligibility criteria for S1011 are met. 

 
S1314 
 
Page 38 
 
Version Date: 7/15/19 
 
 
 
 
e. 
While the protocol plan is for 4 cycles of chemotherapy, patients who receive at 
least three cycles of chemotherapy with cisplatin can go on to protocol cystectomy 
for evaluation purposes, otherwise patients will be removed from protocol 
treatment and the patient can receive a cystectomy off protocol.   
 
7.2 
Arm 1:  Gemcitabine + Cisplatin (GC) Treatment 
 
Treatment should be given in the order listed below: 
 
AGENT 
 
DOSE 
ROUTE 
DAYS 
INTERVAL 
Gemcitabine 
1,000 mg/m2 
IV (over 1 hour)* 
Days 1,8 
21 days x 4 cycles 
Cisplatin 
70 mg/m2 
IV (over 1 hour)* 
Day 1 
21 days x 4 cycles 
In select patients: 
 
 
 
 
Pegfilgrastim** 
6 mg 
SubQ** 
Day 9 
21 days x 4 cycles 
Alternative to 
pegfilgrastim: 
 
 
 
 
Filgrastim*** 
5 mcg/kg 
SubQ/IV*** 
Days 9-13** * 
21 days x 4 cycles 
* While the doses of each drug here are standardized for GC, the duration and timing of 
administration varies regionally and may be given according to institutional practice. 
** One dose given 24-48 hours after completion of chemotherapy for each cycle. 
*** The duration of filgrastim administration may be altered based on patient response or 
institutional practice. 
 
The optional use of growth factor support in Arm 1 should be based on age (notably age 
65 years and older), preexisting conditions (neutropenia at baseline, etc), and other patient 
risk factors for the development of neutropenic fever, pegfilgrastim may be included with 
the first cycle of this regimen at the treating physician’s discretion and institutional practice. 
Additionally, according to your institutional practice, filgrastim may be used as an 
alternative to pegfilgrastim (as outlined in Arm 2) in accordance with your local practice. 
 
 

 
S1314 
 
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Version Date: 7/15/19 
 
 
 
 
7.3 
Arm 2: Dose Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin (DDMVAC) 
Treatment 
 
Treatment should be given in the order listed below: 
 
AGENT 
DOSE 
ROUTE 
DAYS 
INTERVAL 
Methotrexate 
30 mg/m2 
 
IV (over 3 
minutes)* 
Day 1 
 
14 days x 4 
cycles 
 
 
 
 
 
Vinblastine 
3 mg/m2 
IV (over 3 
minutes)* 
Day 1 or 2 
14 days x 4 
cycles 
 
 
 
 
 
Doxorubicin 
30 mg/m2 
IV (over 5 
minutes)* 
Day 1 or 2 
14 days x 4 
cycles 
 
 
 
 
 
Cisplatin 
70 mg/m2 
IV (over 1 hour)* 
Day 1 or 2 
14 days x 4 
cycles 
 
 
 
 
 
Filgrastim 
5 mcg/kg 
SubQ/IV 
Days 3-7** 
14 days x 4 
cycles 
 
 
 
 
 
Alternative to 
filgrastim: 
 
 
 
 
Pegfilgrastim*** 
6 mg 
SubQ*** 
Day 2 or 3 
14 days x 4 
cycles 
* While the doses of each drug here are standardized for DDMVAC, the duration of 
administration varies regionally and may be given according to institutional guideline.   
** On Days 2-6 if all the chemotherapy is given on Day 1. The duration of administration 
may be altered based on patient response or institutional practice.  All patients in Arm 
2 must receive either filgrastim or pegfilgrastim. 
*** One daily dose given 24-48 hours after completion of chemotherapy for each cycle or 
per institutional guidelines.  All patients in Arm 2 must receive either filgrastim or 
pegfilgrastim. 
 
a. 
Use of a PICC line or med-port should be discussed with all patients in Arm 2, as 
this treatment arm includes vesicant with the risk of extravasation.  The timing of 
chemotherapy after either med port or PICC is at the discretion of the treating 
investigator. 
 
b. 
Appropriate pre- and post-hydration for the cisplatin chemotherapy and electrolyte 
replacement including at least 1 liter of pre-hydration solution will be included 
according to institutional guidelines.  Furosemide, mannitol, and electrolyte 
supplementation may be included according to local practices as well.  
 
c. 
With the inclusion of high dose cisplatin, anti-emetic prophylaxis should also be 
administered according to institutional guidelines and are recommended to include 
a corticosteroid, 5-HT3, and NK1 receptor antagonist. 
 
7.4 
Timing of Cystectomy After Chemotherapy 
 
The cystectomy and lymph node dissection must be performed within 70 days from the 
last dose of neoadjuvant chemotherapy with recovery from all associated toxicities to grade 
1 or less at the time of surgery.  At minimum, a standard lymph node dissection must be 
performed at the time of the radical cystectomy.  All potential node bearing tissue should 

 
S1314 
 
Page 40 
 
Version Date: 7/15/19 
 
 
 
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. 
 
7.5 
Criteria for Removal from Protocol Treatment 
 
a. 
Completion of cystectomy 
 
b. 
Unacceptable toxicity.  
 
c. 
Inability to complete protocol chemotherapy due to the following reasons: 
 
• 
A continuous treatment delay for any reason > 3 weeks at any time after 
starting chemotherapy, a cumulative delay in chemotherapy of 4 weeks total, 
or if CrCl is < 50mL/min for one week despite best supportive care and holding 
the chemotherapy.   
• 
More than one dose level reduction for cisplatin or more than two dose level 
reductions for any of the other chemotherapy agents. 
• 
Less than 3 cycles of cisplatin-containing chemotherapy due to toxicity or 
maximum dose reduction reached. 
 
d. 
The patient may withdraw from the study at any time for any reason. 
 
e. 
Patient is no longer a candidate for cystectomy in the opinion of the physician. 
 
7.6 
Discontinuation of Treatment 
 
All reasons for discontinuation of chemotherapy and cystectomy must be documented in 
the S1314 Off Chemotherapy Form and S1314 Cystectomy Status Form. 
 
7.7 
Follow-Up Period 
 
All patients 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 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
4.0 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 4.0. 
 
8.2 
General Dose Modification Considerations 
 
a. 
No dose re-escalations are allowed.  If multiple dose reductions are considered, 
take the lowest level. 
 
b. 
For cisplatin, only one dose level reduction is allowed.  For all other chemotherapy 
agents, two dose level reductions are permitted. 
 

 
S1314 
 
Page 41 
 
Version Date: 7/15/19 
 
 
 
c. 
Any continuous delay in chemotherapy of more than 3 weeks or cumulative delays 
of more than 4 weeks will lead to removal from protocol treatment and referral to 
surgery. 
 
8.3 
Chemotherapy Dose Levels 
 
Dose levels for each chemotherapy agent are shown below.  Please note that once a drug 
dose is reduced, there is no re-escalation to a previous dosing level 
Cisplatin dose levels 
 
Dose level 
CrCl > 59 ml/min 
CrCl > 50 ml/min and <60 ml/min 
Level 0 
70 mg/m2 
35 mg/m2 on Day 1 and Day 8 for 
the Gemcitabine/Cisplatin arm and 
on Days 1 and 2 for the DDMVAC 
arm 
Level -1 
50 mg/m2 
25 mg/m2on Day 1 and Day 8 for the 
Gemcitabine/Cisplatin arm and on 
Days 1 and 2 for the DDMVAC arm 
 
Gemcitabine dose levels  
 
Dose level 
Dose 
Level 0 
1,000 mg/m2 
Level -1 
750 mg/m2 
Level -2 
500 mg/m2 
 
Methotrexate dose levels – myelosuppression and mucositis 
Dose Level 
Dose 
Level 0 
30 mg/m2 
Level -1 
23 mg/m2 
Level -2 
15 mg/m2 
 
Vinblastine dose levels – myelosuppression, nausea, and mucositis 
 
 
 
 
 
 
 
 
 
Dose level 
Dose 
Level 0 
3 mg/m2 
Level -1 
2.3 mg/m2 
Level -2 
1.5 mg/m2 

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S1314 
 
Page 45 
 
Version Date: 7/15/19 
 
 
 
 
c. 
Filgrastim (G-CSF) Dose Modifications 
 
Dose adjustments for toxicities associated with filgrastim (G-CSF) (bone pain, 
splenomegaly, abnormalities in uric acid concentrations, LDH and alkaline 
phosphatase, transient elevations of serum creatinine and aminotransferase 
activity) 
 
Dose modifications for G-CSF toxicity should only be initiated if 
symptomatic control of the toxicity fails (i.e., analgesics such as 
acetaminophen or acetaminophen with codeine for myalgias or bone pain, 
etc.). 
Toxicity Grade 
Dose Adjustment 
Grade 0 - 1 
No change 
 
Grade 2 
Decrease G-CSF to 3 mcg/kg/d 
 
Grade 3 - 4 
Discontinue G-CSF 
 
8.5 
Dose Modifications Contacts 
 
For dose modification questions, please contact Dr. Thomas W. Flaig at 303/724-0499 
(S1314question@swog.org) 
or 
Dr. 
Siamak 
Daneshmand 
at 
323/865-3700 
(S1314question@swog.org). 
 
8.6 
8Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 

 
S1314 
 
Page 46 
 
Version Date: 7/15/19 
 
 
 
9.0 
STUDY CALENDAR 
9.1 
Arm 1 GC – Study Calendar – 21 day cycles  
 
(a) 
 (c) 
PHYSICAL 
Pre-
study 
C1D1 
C1D8 
C2D1 
C2D8 
C3D1 
C3D8 
C4D1 
C4D8 
Pre-Surgery 
Surg 
F/U prior 
to prog 
F/U post 
prog 
History and physical (with 
BSA, BP, and wt) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
Performance status  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
Toxicity notation 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X(f) 
X(g) 
Total bilirubin 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
AST and ALT 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
Alkaline phosphatase 
X(e) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
Magnesium (h) 
X(e) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
Phosphorus (h) 
X(e) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(f) 
X(g) 
Serum creatinine 
X(e) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X(f) 
X(g) 
Electrolytes (sodium, 
potassium, chloride, 
bicarbonate (or CO2) 
X(e) 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Blood urea nitrogen (BUN) 
X(e) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Glucose 
X(e) 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Pregnancy test (b) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STAGING 
 
 
 
 
 
 
 
 
 
 
 
 
 
TURBT and bimanual exam  
X 
 
 
 
 
 
 
 
 
 
 
 
 
CORRELATIVE SAMPLES 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 (10 micron) slides plus 2 
(5 micron) slides at start & 
stop of 20 slide cut from 
TURBT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
20 (10 micron) slides plus 2 
(5 micron) slides at start & 
stop of 20 slide cut from 
cystectomy 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Arm 1 continued on next page.  Footnotes for Arm 1 on next page. 
 
 

 
S1314 
 
Page 47 
 
Version Date: 7/15/19 
 
 
 
9.1 
Arm 1 GC – Study Calendar – 21 day cycles  (contd.) 
 
Footnotes for Arm 1 
(a) 
Pre-study lab results may be used if within 3 days prior to Cycle 1, Day 1  
(b)  
For women of childbearing potential; to be done within 7 days prior to registration – see Section 5.3i. 
(c) 
Within 70 days from the last dose of neoadjuvant chemotherapy (see Section 7.4) 
(d) 
A bone scan should only be performed if there is presence of suspicious bone pain, or other clinical suspicion – see Section 5.1d.  
(e) 
A baseline value should be collected at prestudy; these tests are not required for eligibility purposes. 
(f) 
F/U procedures (prior to progression): CT or MRI of the abdomen & pelvis, CT of the chest or 2-view chest x-ray, and physical exam/history 
and laboratory assessments-every 3 months for one year, then every 6 months for 2 years, then annually until 5 years from registration. 
(g) 
F/U procedures (post progression):  Physical exam/history and laboratory assessments -every 3 months for one year, then every 6 months 
for 2 years, then annually until 5 years from registration. 
(h) 
Phosphorus and magnesium monitoring are recommended every cycle, but may be omitted at the discretion of the treating medical provider. 
(i) 
In select patients:  Pegfilgrastim 6 mg SubQ Day 9 of each cycle. Alternative to pegfilgrastim: Filgrastim 5 mcg/kg SubQ/IV Days 9-13. 
(j) 
1 EDTA tube and 1 DNA Streck tube (in kit provided) should be collected pre-treatment on C1D1 and C2D1. 
 
Allowable windows 
Allowable windows for scheduled procedures and assessments performed every 7-14 days is +/- 1 day, every 21 days is +/- 3 days, every 3-6 
months is +/- 7days, and every year is +/- 14 days.  The window is to be calculated from the scheduled date of the procedure/assessment 
Treatment should begin within 14 days of randomization. 
 
 
 
 
(a) 
 
 
 
 
 
 
 
 
(c) 
 
 
PHYSICAL 
Pre-
study 
C1D1 
C1D8 
C2D1 
C2D8 
C3D1 
C3D8 
C4D1 
C4D8 
Pre-
Surgery 
Surg 
F/U prior 
to prog 
F/U post 
prog 
CORRELATIVE 
SAMPLES (cond.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
CTC blood samples (j) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Biomarker blood samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker urine sample 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI of the 
abdomen and pelvis 
X 
 
 
 
 
 
 
 
 
X 
 
X(f) 
 
CT of the chest or 2- view 
chest X-ray 
X 
 
 
 
 
 
 
 
 
X 
 
X(f) 
 
Whole body bone scan (d) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT (i) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cisplatin 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Gemcitabine  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 

 
S1314 
 
Page 48 
 
Version Date: 7/15/19 
 
 
 
9.2 
Arm 2 DDMVAC – Study Calendar – 14 day cycles  
 
 
(a) 
 
 
 
 
 
 
 
 
(c) 
 
 
PHYSICAL 
Pre-
study 
C1D1 
C1D2 
C2D1 
C2D2 
C3D1 
C3D2 
C4D1 
C4D2 
Pre-
Surg 
Surg 
F/U prior 
to prog 
F/U post 
prog 
History and Physical (with BSA, 
BP, & wt) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Performance status  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Toxicity notation 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Total bilirubin 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
AST and ALT 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Alkaline phosphatase 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Magnesium (j) 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Phosphorus (j) 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Serum creatinine 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Electrolytes (sodium, potassium, 
chloride, bicarbonate (or CO2) 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Glucose 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Calcium 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Albumin 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Total protein 
X(g) 
X 
 
X 
 
X 
 
X 
 
X 
 
X(h) 
X(i) 
Pregnancy test (b) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STAGING 
 
 
 
 
 
 
 
 
 
 
 
 
 
TURBT and bimanual exam  
X 
 
 
 
 
 
 
 
 
 
 
 
 
CORRELATIVE SAMPLES 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 (10 micron) slides plus 2 (5 
micron) slides at start & stop of 
20 slide cut from TURBT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
20 (10 micron) slides plus 2 (5 
micron) slides at start & stop of 
20 slide cut from cystectomy 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CTC blood samples (k) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
9.2 Calendar continued on next page.  Footnotes for Arm 2 on next page 

 
S1314 
 
Page 49 
 
Version Date: 7/15/19 
 
 
 
9.2 
Arm 2 DDMVAC – Study Calendar – 14 day cycles (contd.) 
 
Footnotes for Arm 2:  
(a) Pre-study lab results may be used if within 3 days prior to Cycle 1, Day 1. 
(b) For women of childbearing potential; to be done within 7 days prior to registration – see Section 5.3i. 
(c) Within 70 days from the last dose of neoadjuvant chemotherapy (see Section 7.4). 
(d) A bone scan should only be performed if there is presence of suspicious bone pain, or other clinical suspicion – see Section 5.1d.  
(e) Cisplatin, vinblastine and doxorubicin may be given on Day 2 alternatively with filgrastim starting 24-48 hours after the chemotherapy infusion is finished. 
(f) Pegfilgrastim is to be given 24-48 hours after the chemotherapy is completed.  Alternatively, filgrastim may be given daily for 5 days starting 24-48 hours 
after the chemotherapy is complete.   
(g) A baseline value should be collected at prestudy; these tests are not required for eligibility purposes. 
(h)  Follow-up procedures (prior to progression):  CT or MRI of the abdomen & pelvis, CT of the chest or 2-view chest x-ray, and physical exam/history and 
laboratory assessments – every 3 months for one year, then every 6 months for 2 years, then annually until 5 years from registration. 
(I) Follow-up procedures (post progression):  Physical exam/history and laboratory assessments every 3 months for one year, then every 6 months for 2 years, 
then annually until 5 years from registration. 
(j) 
Phosphorus and magnesium monitoring are recommended every cycle, but may be omitted at the discretion of the treating medical provider. 
(k) 1 EDTA tube and 1 DNA Streck tube (in kit provided) should be collected pre-treatment on C1D1 and C2D1. 
Allowable windows 
Allowable windows for scheduled procedures and assessments performed every 7-14 days is ± 1 day, q 21 days is ± 3 days, q 3-6 months is ± 7days, and q year 
is ± 14 days. The window is to be calculated from the scheduled date of the procedure/assessment. Treatment should begin within14 days of randomization. 
 
 
(a) 
 
 
 
 
 
 
 
 
(c) 
 
 
PHYSICAL 
Pre-study 
C1D1 
C1D2 
C2D1 
C2D2 
C3D1 
C3D2 
C4D1 
C4D2 
Pre-
Surg 
Surg 
F/U prior 
to prog 
F/U post 
prog 
CORRELATIVE SAMPLES (contd.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker blood samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker urine sample 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI of ABD/pelvis 
X 
 
 
 
 
 
 
 
 
X 
 
X(h) 
 
CT/chest or 2-view chest X-ray 
X 
 
 
 
 
 
 
 
 
X 
 
X(h) 
 
Whole body bone scan (d) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Ejection Fraction (see 
Section 5.3b) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT (e) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Methotrexate 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Cisplatin 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Vinblastine 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Doxorubicin 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Filgrastim (or Pegfilgrastim) (f) 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Recurrence criteria 
 
Criteria for recurrence will include measurable disease on cross-sectional imaging or plane 
radiography targeting lung, liver and bone as most common sites for recurrence.  Bone 
scintigraphy may be used according to Good Medical Practice and is recommended with 
confirmed elevation in the alkaline phosphatase. Local pelvic recurrence may be 
determined by cross-sectional imaging and/or DRE (and confirmed by biopsy if indicated). 
PET/CT may be used to confirm suspicious abnormalities on other imaging modalities. 
 
10.2 
Recurrence-Free Survival 
 
To be estimated in a subset of patients who received protocol cystectomy. The recurrence-
free time interval is from date of cystectomy to date of first documentation of 
relapse/recurrence or death due to any cause.  Patients last known to be alive without 
report of relapse/recurrence are censored at date of last contact. 
 
10.3 
Overall Survival 
 
Overall survival is measured from date of randomization to date of death from any cause.  
Patients known to be alive are censored at date of last contact. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT  
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (e.g. light housework, office work). 
 
2 
Ambulatory and capable of self-care, but unable to carry out any work 
activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair 
 
10.5 
Pathologic Response 
 
 
Pathologic staging is based on the operative and pathology report from cystectomy at the 
local site. (58)  Patients not undergoing a cystectomy will be judged to be a nonresponder.   
 
TX  
Primary tumor cannot be assessed.  
T0  
No evidence of primary tumor.  
Ta  
Noninvasive papillary carcinoma.  
Tis  
Carcinoma in situ: "flat tumor."  
T1  
Tumor invades subepithelial connective tissue. 
T2  
Tumor invades muscularis propria.  
pT2a  Tumor invades superficial muscularis propria (inner half).  
pT2b  Tumor invades deep muscularis propria (outer half).  

 
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T3  
Tumor invades perivesical tissue.  
pT3a  Microscopically.  
pT3b  Macroscopically (extravesical mass).  
T4  
Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, 
vagina, pelvic wall, abdominal wall.  
T4a  
Tumor invades prostatic stroma, uterus, vagina.  
T4b  
Tumor invades pelvic wall, abdominal wall. 
 
NX  
Lymph nodes cannot be assessed.  
N0  
No lymph node metastasis.  
N1  
Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, 
external iliac, or presacral lymph node).  
N2  
Multiple regional lymph node metastases in the true pelvis (hypogastric, obturator, 
external iliac, or presacral lymph node).  
N3  
Lymph node metastases to the common iliac lymph nodes. 
 
M0  
No distant metastasis.  
M1  
Distant metastasis 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual Goal 
 
Two treatment-specific COXEN gene signatures will be evaluated for prognostic and 
predictive significance using pathologic response to neoadjuvant chemotherapy as the 
endpoint of interest.  We will look at both pathologic complete response (pT0) and 
pathologic favorable downgrading (≤ pT1 [pT0, pTa, pTis]).  We expect to randomize 184 
eligible patients with adequate tissue submission for COXEN assessment who received at 
least 3 cycles of chemotherapy, and are assessable for pT0 status or have clinical 
progression.  To account for ineligibles, inadequate specimens and non-evaluable patients, 
we will over-accrue by 25% so the total accrual goal is 230 patients.  We assume it will 
take 3.5 years of accrual (71 patients/yr) to reach this goal. 
 
11.2 
Analysis of Primary Endpoint 
 
The two established COXEN gene signatures that were developed for each chemotherapy 
regimen will be evaluated using each patient’s tissue from the TURBT, regardless of 
treatment arm assignment.  Thus, each patient will have a DDMVAC-GEP and a GC-GEP.  
The two GEPs are fully specified from the analysis of prior bladder cohorts predicting 5-
year survival (see Section 2.0 of the protocol for details).  We know from SWOG’s neo-
adjuvant chemotherapy trial (S8710) that the pT0 rate among all patients randomized to 
MVAC (assuming those without a cystectomy were not pT0) was 31%, and attaining a pT0 
was highly correlated with superior survival. (64)  We went back to the Laval and Lehmann 
combined bladder cohorts that were used to both develop the gene signatures and validate 
them in order to identify the 5-year predicted survival cut-point from the DDMVAC-GEP 
and GC-GEP for the top 31% of predicted favorable survivors.  If a patient in S1314 has a 
treatment-specific GEP that provides a 5-year predicted probability greater than or equal 
to that treatment-specific threshold, we will assume that also predicts for a pT0 at 
cystectomy.  An examination of stage-specific COXEN score “cutoffs” will be performed as 
part of an exploratory analysis. 
 
Data from the 184 patients (92/arm) will be used to evaluate the association of each GEP 
with pT0 and secondary downgrading outcomes within each treatment-specific group.  This 
will evaluate the prognostic significance of each treatment-specific GEP within each 
treatment group.  Since this is a Phase II trial and assessments are exploratory, there will 

 
S1314 
 
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not be adjustment for multiple testing.  If there is later found to be no interaction between 
the treatment-specific GEP and treatment arm, then data from both treatment arms can be 
combined to evaluate the prognostic association of each GEP with pT0 assessment.  By 
using the continuous distribution of the GEP, we will increase our power to evaluate 
associations.  When applying COXEN to DDMVAC-treated patients in the bladder cancer 
setting, the COXEN GEP has previously yielded a sensitivity and specificity of 83% and 
64%, respectively in a neo-adjuvant MVAC chemotherapy dataset in bladder cancer. (65)  
For modeling considerations, we lack specificity and sensitivity values for the GC GEP in 
this clinical situation, so we will make the same assumptions for GC that we did for 
DDMVAC.  Based on prior bladder cancer paired GEP data, we do not expect there to be 
a large overlap of patients who will have both a favorable GC-GEP and a favorable 
DDMVAC-GEP in terms of predicting 5-year survival and pT0 status. 
 
11.3 
Analysis of Secondary Endpoints 
 
The validity of the COXEN score threshold that was identified in a previous bladder cohort 
will be assessed by evaluating the association of COXEN score (low vs. high) for the 
outcome of pT0 (Y/N) in a multivariate logistic regression model that also will include age, 
gender, clinical T-stage, and grade.  Applying a one-sided alpha of 0.05 and using 92 
patients for each treatment arm comparison, there will be 99% statistical power to detect 
differences in pT0 rates such as that specified in Table 2 where the absolute difference in 
the pT0 rate between the predicted responders and non-responders is 50%.  There will be 
82% power to detect differences in the absolute range of 30% (e.g., 22% vs. 52%). 
 
Table 2: 
 
Predicted 
Responder 
from 
Treatment-Specific Gene Expression 
Profiling 
Total 
Path Response 
Yes 
No 
 
pT0 
24 (52%) 
6 (13%) 
33%  (n=30) 
No pT0 
22 
40 
67%  (n=62) 
 
46 
46 
N=92 for each 
treatment arm analysis 
Sensitivity=80%, specificity=65% 
 
A similar modeling approach will be used to evaluate the outcome of favorable 
downgrading as a secondary endpoint.  Although statistical power will be low, we are also 
interested in whether there is any suggestion that the treatment-specific GEP is a predictive 
factor for pT0 status.  That is, can the treatment specific GEP score help to direct which of 
the two neoadjuvant treatment regimens the patient should receive?  Each of the two 
treatment-specific GEPs will be evaluated in separate analyses.  In order to evaluate each 
GEP's predictive property, all 182 patients will be included in a logistic regression model.  
For illustrative purposes, we will specify the process for the DDMVAC-specific GEP 
analysis.  Indicators for age group, gender, clinical T-stage, grade, treatment arm, and 
indicator for favorable DDMVAC-specific GEP score will be placed in the model along with 
an interaction term of treatment arm x DDMVAC GEP indicator.  Testing this interaction is 
equivalent to testing whether those with a favorable DDMVAC GEP score who receive 
DDMVAC have greater odds of the pT0 outcome compared to those with a favorable GEP 
score who were randomized to GC. This differentiates the GEP score as predictive in 
contrast to prognostic. 
 
If we assume the pT0 rate will be the same for both treatment arms and will be 31%, and 
we assume that a favorable GEP score (split at 31% for this example in order to illustrate 
power) has an odds ratio of 1.2 for the GC arm (prognostic strength), and using a two-
sided type I error rate, then there will be 60% power to detect a very large interaction term 

 
S1314 
 
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Version Date: 7/15/19 
 
 
 
of 5.5.  That would imply that the odds ratio for the favorable DDMVAC- GEP score group 
compared to unfavorable is 5.5 times greater if the patient gets DDMVAC treatment 
compared to GC.  A similar analysis will also be conducted for the GC-specific GEP, 
assessing whether it’s predictive.  Statistical properties will be similar. 
 
Regardless of the predictive properties of either GEP score, being able to identify a subset 
of patients with poor prognosis based on their GEP score will have a meaningful clinical 
impact.  Our goal is to find a group of patients with chemotherapy resistant disease for 
whom the risk of progression is so great that they would likely benefit from going directly 
to surgery and not receiving neoadjuvant therapy.  Conversely, identifying groups of 
patients who have a high probability of benefiting from neoadjuvant chemotherapy will 
allow physicians to better evaluate the risks of delaying surgery to deliver chemotherapy. 
If we assume there is no interaction between GEP score and treatment arm, then we will 
pool all 184 patients together to evaluate the prognostic properties of each GEP with 
respect to overall survival.  We assume median survival (both arms) for those with an 
unfavorable score will be 40 months, and we expect half the patients will have a favorable 
GEP score.  If we assume 3 years of accrual, an additional 3 years of follow-up, and a two-
sided alpha=0.05 then we will have 83% power to detect a  hazard ratio of 1.90 between 
those with an unfavorable GEP score relative to the favorable group.  This is comparable 
to a median OS of 40 months versus 76 months. The absolute level of the survival curves 
as well as their degree of separation will be important in this setting. 
 
There will be no formal interim analyses since the objective of this trial is not to directly 
compare the two treatment regimens as both could be considered standard-of-care.  The 
final analysis using the pathologic response endpoint is expected approximately one year 
after the last patient has been randomized or four years after study activation.  Subsequent 
analyses related to survival will occur 3-4 years after accrual is completed. 
 
11.4 
Data and Safety Monitoring Committee Oversight 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center, and will meet at 
the Group's bi-annual meetings as necessary.  The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study. 
 
Note: The specific statistical considerations for the TM studies can be found in Appendix 
18.3.   
 
 
12.0 
DISCIPLINE REVIEW 
 
There will be no formal discipline review done in conjunction with this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than 14 days prior to 
planned start of treatment). 
 
 

 
S1314 
 
Page 54 
 
Version Date: 7/15/19 
 
 
 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet (FDA Form 1572 with original signature, current 
CV, Supplemental Investigator Data Form with signature and Financial Disclosure Form 
with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI.  
These forms are available on the CTSU Web site (enter credentials at https://www.ctsu.org; 
then click on the Register tab) or by calling the PMB at 240/276-6575 Monday through 
Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each investigator or group of investigators at a clinic site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can enroll patients.  Study centers can check the status of their 
registration packets by querying the Regulatory Support System (RSS) site registration 
status page of the CTSU member web site by entering credentials at https://www.ctsu.org.  
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Oncology Patient Enrollment Network (OPEN) will also ask additional questions that are 
not present on the SWOG Registration Worksheet.  The individual registering the patient 
must be prepared to provide answers to the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Cooperative Group Credit 
 
f. 
Credit Investigator 
 
g. 
Patient Initials 
 
h. 
Patient’s Date of Birth 
 
i. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
j. 
Country of Residence 
 
k. 
ZIP Code 
 
l. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
 

 
S1314 
 
Page 55 
 
Version Date: 7/15/19 
 
 
 
m. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
n. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
o. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this 
study.  OPEN is a web-based application and can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes 
and the affirmation of eligibility on the Registration Worksheet has been 
signed 
by 
the 
registering 
investigator 
or 
another 
investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
• 
The study site is listed as “approved” in the CTSU RSS. 
 
c. 
Access requirements for OPEN: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user ID and password) 
used for the CTSU members’ web site.  
 
• 
To perform registrations, the site user must have been assigned the 
‘Registrar’ role on the SWOG or CTSU roster:  
 

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S1314 
 
Page 58 
 
Version Date: 7/15/19 
 
 
 
c. 
IF PATIENT CONSENTED, WITHIN 24 HOURS OF C1D1 AND C2D1 OF 
CHEMOTHERAPY 
 
Submit specimens as outlined in Section 15.2 
 
d. 
WITHIN 7 DAYS AFTER EACH CYCLE OF CHEMOTHERAPY: 
 
Submit the following: 
 
S1314 Treatment Form 
 
S1314 Adverse Event Form 
 
e. 
WITHIN 14 DAYS OF DISCONTINUATION OF CHEMOTHERAPY: 
 
Submit the following: 
 
S1314 Treatment Form 
 
S1314 Adverse Event Form 
 
S1314 Off Chemotherapy Notice 
 
f. 
WITHIN 14 DAYS OF COMPLETION OF CYSTECTOMY: 
 
Submit the following: 
 
If patient received protocol cystectomy 
 
S1314 Cystectomy Status Form 
 
S1314 Cystectomy Reporting Form 
 
Operative report from cystectomy 
 
Pathology report from cystectomy 
 
If patient received cystectomy off protocol 
 
S1314 Cystectomy Reporting Form 
 
Operative report from cystectomy 
 
Pathology report from cystectomy 
 
g. 
WITHIN 14 DAYS OF DECISION TO NOT HAVE PROTOCOL CYSTECTOMY: 
 
Submit the following: 
 
S1314 Cystectomy Status Form 
 
h. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE:: 
 
If patient was still on protocol chemotherapy 
 
Submit the following: 
 
S1314 Off Chemotherapy Notice 
 

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S1314 
 
Page 63 
 
Version Date: 7/15/19 
 
 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for timelier monitoring of patient 
safety and care.  The following guidelines prescribe expedited adverse event 
reporting for this protocol. See also Appendix 18.1 for general and background 
information about expedited reporting. 
 
b. 
Reporting method 
 
This study requires that expedited adverse event reporting use the Cancer 
Therapy Evaluation Program Adverse Event Expedited Reporting System (CTEP-
AERS). 
 
CTEPs 
guidelines 
for 
CTEP-AERS 
can 
be 
found 
at 
http://ctep.cancer.gov.  A CTEP-AERS report must be submitted to the SWOG 
Operations Office electronically via the CTEP-AERS web-based application 
located at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_ev
ents.htm.  
 
In the rare event when internet connectivity is disrupted an electronic report MUST 
be submitted immediately upon re-establishment of internet connection.   
 
c. 
When to report an event in an expedited manner 
 
When the adverse event requires expedited reporting, submit the report within 10 
calendar days of learning of the event. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required.  
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures.  
 
 

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17.0 
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43  
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45  
Hoffmann AC, Wild P, Leicht C, et al.  MDR1 and ERCC1 expression predict outcome of patients 
with locally advanced bladder cancer receiving adjuvant chemotherapy.  Neoplasia 12:628-36, 
2010. 
 
46  
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61  
Williams PD, Cheon S, Havaleshko DM, et al. Concordant gene expression signatures predict 
clinical outcomes of cancer patients undergoing systemic therapy.  Cancer Res 69:8302-9, 2009. 
 
62  
Williams PD, Cheon S, Havaleshko DM, et al. Concordant gene expression signatures predict 
clinical outcomes of cancer patients undergoing systemic therapy.  Cancer Res 69:8302-9, 2009. 
 
63  
Williams PD, Cheon S, Havaleshko DM, et al. Concordant gene expression signatures predict 
clinical outcomes of cancer patients undergoing systemic therapy.  Cancer Res 69:8302-9, 2009. 
 
64  
Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy 
compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-66, 
2003. 
 
65  
von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, 
vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, 
randomized, multinational, multicenter, phase III study.  J Clin Oncol 18:3068-77, 2008. 
 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
New York Heart Association Classifications 
 
18.2 
Pathological Verification of Tissue Submission Form 
 
18.3 
Translational Medicine Studies 
 
a. 
microRNA Expression Profile 
b. 
Ultra Pure Circulating Tumor Cells Using Coxen 
c. 
Cisplatin Germline Pharmacogenomic 
d. 
DNA Damage Response to Gene Alterations 
 
18.4 
Circulating Tumor Cell (CTC) Instructions for Blood Sample Processing, Packing and 
Shipping 
 
 
 

 
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18,1 
New York Heart Association Classifications 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
** At accustomed occupation or usual tasks. 
 
 
 
 

 
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18.2 
Pathological Verification of Tissue Submission Form 
 
SWOG Patient Identifier: _____________ Patient Initials: ______ (L, F, M) 
   
Pathology Diagnosis: _______________________________________________ 
 
Specimen Review 
 
Viable Tumor Size in Submitted Slides (PLEASE CHECK ONLY ONE): 
 
□Adequate (≥ 0.5 cm of viable tumor-longest diameter)  
□Inadequate (< 0.5 cm of viable tumor), patient is ineligible 
 
 
 
____________________________________ _______________ 
Pathologist  
 
 
 
 
Date 
 
NOTE: This form must be signed by pathologist and submitted as source documentation 
via the Web using Medidata Rave.  
 
Comments: 
 
 
 

 
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18.3 
Translational Medicine Studies  
 
Objectives 
 
1. To assess microRNA expression profile. 
2. To assess Ultra Pure CTC 
3. To assess Cisplatin germline pharmacogenomics 
4. To assess DNA damage response to gene alterations   
5. To assess other translational endpoints via gene expression, tissue microarray, 
microRNA, SNP and genetic profiling data collected in the neoadjuvant bladder cancer 
setting.  (The pre-chemotherapy TURBT sample and the post-chemotherapy 
cystectomy samples will be tested for mRNA, genetic, SNP, and microRNA 
expression.  Additionally, blood, urine and tissue for tissue microarray will be obtained.)   
 
Analysis of Translational Medicine (TM) Endpoints 
 
Biologic samples for this study will be collected via the consolidated SWOG Biorepository 
at Nationwide Children's Hospital Biopathology Center in Columbus, Ohio. Study protocols 
for non-COXEN studies currently described in Section 18.3a-18.3d. There will be three 
types of biologic samples, with a prioritization schedule for each, delineated below.  Of 
note, the principle of analyses will be to perform a global evaluation of a specific metric 
(e.g. RNA), which can be applied to the specific hypothesis being tested in the trial but will 
also be released after this prescribed assessment to the general research community for 
use.  For example, gene expression will be assessed on all of the TURBT samples, the 
COXEN scores will be calculated/reported, and then the gene expression data linked to 
clinical outcomes will be released for general use.  
 
TURBT: 
1. 
RNA (COXEN GEM + microRNA) 
2. 
DNA (Oncogenomic) 
3. 
With additional tissue for future studies as available 
 
Residual tumor at cystectomy:  
1. 
RNA (COXEN GEM, microRNA) 
2. 
DNA  (Oncometrics) 
3. 
With additional tissue for future studies as available 
 
Blood sample:  
1. 
DNA (Oncogenomic)  
2. 
Cisplatin pharmacogenomics)  
3. 
With additional samples for future studies as available 
 
 
 

 
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18.3a  microRNA (miRNA) expression profile 
 
Objective 
1.  
To explore whether there is a miRNA expression profile that correlates with 
pathologic complete response, a pathologic downstaging or the lack thereof after 
TURBT and neoadjuvant chemotherapy with either GC or DDMVAC. 
 
Study Design  
 
microRNA (miRNA) expression profile – 20 (10 micron) slides plus 5 micron slides at start 
and stop of 20 slide cut.  The 5 micron slides will be stained with H&E centrally, and a 
pathologist will use it to mark the tumor area(s).  Using the H&E as a template, the tumor 
areas on the remaining (unstained) slides are manually removed to microcentrifuge tubes 
for RNA isolation.  Total RNA is  isolated  using  the  total  RNA  isolation  method  in  the  
High  Pure  miRNA  isolation  Kit  (catalog  number 05080576001, Roche Applied Science).  
A NanoDrop ND-1000 spectrophotometer (Thermo Scientific) and an Agilent 2100 
Bioanalyzer are used to measure RNA purity and integrity. Total RNA is used for the 
synthesis of biotinylated cDNA that is annealed to assay specific oligonucleotides and 
captured on streptavidin-conjugated paramagnetic particles.  After extension and ligation, 
the ligated oligonucleotides are labeled with fluorescent primers by PCR, and these PCR 
products are hybridized to Illumina HT12V4 chips.  After being washed, the slides are 
scanned with BeadStation 500X (Illumina, Inc.) and the signal intensities are quantified 
with GenomeStudio (Illumina, Inc.). Quantile normalization in the Linear Models for 
Microarray Data (LIMMA) package in the R language environment is used to normalize the 
data. 
 
Specific hypotheses  
 
• 
To explore whether there is a miRNA expression profile that correlates with 
pathologic complete response, pathologic downstaging or the lack thereof after 
TURBT and neoadjuvant chemotherapy with either GC or DDMVAC. 
 
MicroRNAs play a central role in the regulation of EMT, particularly members of the miR200 
family and miR205, and in preliminary analyses of 34 tumors from patients treated with 
neoadjuvant MVAC at MD Anderson, we have discovered that the miR200 family and 
miR205 identify subsets of tumors that are enriched for response to therapy (downstaging 
to ≤ pT1). With our optimization of Ion Torrent’s Ampliseq platform for miRNA sequencing 
from FFPE tissue sections, it has become just as cost-effective and feasible to use micro 
RNA sequencing to measure the expression of all micro RNAs as it is to perform a more 
focused quantitative real-time PCR analysis of the expression of specific miRNAs. 
Furthermore, we recently developed a micro RNA-based PAM classifier that can be used 
to assign bladder cancers to the 4 known intrinsic subtypes, including “p53-like” tumors 
that are resistant to neoadjuvant chemotherapy. The focus of our studies will be to 
prospectively examine the relationship between intrinsic subtype membership as 
determined by miRNA expression profiling and pathological response within the context of 
this clinical trial. This work will complement the p53 sequencing studies discussed below. 
 
Whole genome micro RNA expression will be determined by sequencing (Ion Torrent 
platform).  The amount of small RNA in the total RNA sample is quantified with the use of 
Small RNA and RNA 6000 Nano bioanalyzer chips from Life Technologies. Twenty ng of 
small RNA is used for library preparation with the Ion Total RNA Seq v2 library preparation 
kit. The resulting cDNA library is quantified with High Sensitivity DNA bioanalyzer chips 
from Life Technologies to determine the molar concentration of each library, and to 
calculate the percentage of library that represents barcoded small RNAs. The cDNA 
libraries are diluted to the same molar concentration, pooled, and diluted to 100 pM. The 
samples are then templated and sequenced with an Ion Proton sequencer.  The normalized 

 
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micro RNA sequencing data will be used to first assign tumors to the intrinsic basal and 
luminal subtypes using a PAM classifier.  A 15-gene micro RNA panel will then be used to 
divide the basal and luminal tumors based on EMT and fibroblast infiltration as described 
previously. (1)   
 
Statistical design  
 
General strategies for the analyses of these projects will proceed by the following 
principles.  As this is only a Phase II trial, the aims being addressed are hypothesis-building 
in nature, and any findings will need to be validated in another bladder cohort.  Because 
both treatment arms involve neoadjuvant chemotherapy including cisplatin, it will not be 
possible to attribute lack of response as resistance to chemotherapy or particularly 
cisplatin.  These tumors may have poor prognosis and be resistant to any current treatment 
options.  We can only interpret significant factors as being prognostic for pathologic and 
clinical outcomes. 
 
For most of these hypotheses, it will be reasonable to pool the treatment arms as both 
neoadjuvant chemotherapy regimens contain cisplatin and relationships of markers with 
pathologic response, RFS and OS are expected to be similar for DDMVAC and GC-treated 
patients.  The exception to this will be the COXEN GEP analysis where the detailed 
analysis of the treatment interaction is specified in Section 11.0 of this protocol. 
 
Measures of expression – miRNA expression data and stem, progenitor and differentiation 
markers will likely be log- transformed before any analysis.  Quantile normalization in the 
Linear Models for Microarray Data (LIMMA) package in the R language environment is 
used to normalize the data.  BRB ArrayTools version 4.2 developed by National Cancer 
Institute is used to analyze the data.  This software uses a two-sample t-test to calculate 
the significance of the observations with false discovery rate (FDR) (i.e., P < 0.001).  To 
predict the class of an independent data set, we developed a model based on Nearest 
Neighbor Classification (k=1, k=3).  The prediction error of a model was estimated using 
leave one out cross-validation (LOOCV).  For LOOCV training set, the entire model building 
process was repeated, including the gene selection process.   We also evaluated whether 
the cross-validated error rate estimate for a model was significantly less than one would 
expect from random prediction. 
 
Exploratory analyses will be performed to examine the underlying distributions using box 
plots, density plots, and scatter plots.  For assessment of relationship with pathologic 
response (both pT0 and <pT1), logistic regression will be conducted upon tens of 
thousands of values simultaneously, adjusting for the stratification factors from the trial.  
False discovery rate (FDR) will be used to control the average false positive proportions 
among selected measures. 
 
 

 
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18.3b  Ultra Pure Circulating Tumor Cells Using Coxen 
 
Objective 
 
To assess whether the COXEN gene expression profiles of ultra-pure circulating tumor cells 
(upCTCs) predict response (T0) to neoadjuvant chemotherapy at cystectomy. 
 
Hypothesis and Specific Aims 
 
Locally advanced bladder cancer has high recurrence and mortality rates despite surgical 
intervention. Neoadjuvant chemotherapy prior to resection improves outcomes in some patients 
but causes unnecessary morbidity and delays surgery in others. S1314 is a SWOG trial testing the 
value of COXEN, a gene expression profiling strategy that aims to predict chemotherapy response. 
Currently, COXEN and other gene expression panels are measured from tumor biopsies, but such 
tissue is rarely available in advanced metastatic disease. An emerging alternative is enrichment of 
circulating tumor cells (CTCs) from the blood of patients with advanced disease, allowing minimally 
invasive, repeated sampling of tumor cells to guide precision care. Our laboratory has developed 
and implemented multiple techniques for enriching and molecularly characterizing circulating tumor 
cells (CTCs) in clinical trial settings and founded a CTC Research Core at USC Norris. Most 
recently, we have incorporated new technologies and methods that for the first time allow not only 
DNA analysis, but also enrichment of ultra-pure cells (upCTCs) for gene expression profiling 
without white blood cell (WBC) contamination. The convergence of our upCTC technology with 
S1314/COXEN offers a unique translational science opportunity to test the hypothesis that CTC 
gene expression can predict chemotherapy response. To test this hypothesis we will collect and 
enrich upCTCs at two time points (before and after start of chemotherapy) in S1314 and extract 
mRNA from upCTCs for the following Specific Aims (Figure 1): 
 
1. 
We will assess whether the COXEN gene expression profiles of upCTCs predict 
response (T0) to neoadjuvant chemotherapy at cystectomy. 
 
2. 
We will test the association between upCTC-derived COXEN gene expression 
profiles and tumor biopsy-derived COXEN gene expression profiles. 
 
3. 
We will analyze the change in upCTC-derived COXEN gene expression profile 
before vs. after chemotherapy. 
 
4. 
(Exploratory) upCTC-derived DNA will be isolated for targeted sequencing and 
correlated with COXEN scores and with matched primary tumor DNA (beyond 
immediate study scope. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SIGNIFICANCE AND INNOVATION 
 
• 
Advances a key area in translational precision cancer care: Expands the role of CTC 
analysis from its current state (DNA analysis) to the realm of CTC gene expression profiling, 
enabling new insights into real- time tumor response during and after treatment 
 
Unique trial opportunity: S1314 allows comparison of CTC and tumor phenotypes before and after 
therapy, establishing a potential biomarker role for CTC gene expression in precision cancer care 
 
BACKGROUND AND PRELIMINARY DATA 
 
Bladder Cancer: Cancer of the urinary bladder is an aggressive malignancy that will account for 
75,000 new cases and 15,000 deaths in the U.S. in 2014. (2) Tumors arise in the mucosal 
epithelium that lines the bladder lumen, and the standard treatment for tumors that invade 
beyond the mucosa (T2-T4) is radical cystectomy. Despite this aggressive surgical approach, 
within 2 years approximately half of patients develop recurrent metastatic disease that is 
invariably lethal. (3) Use of neoadjuvant chemotherapy prior to radical cystectomy has been 
shown to improve overall survival and reduce recurrence rates, in particular when the resected 
bladder is found to contain no viable tumor (T0) after chemotherapy. (4) However, neoadjuvant 
chemotherapy is effective only in some tumors, while in others it may only create a delay prior 
to radical cystectomy, perhaps allowing time for spread of disease that otherwise would have 
been curable with immediate resection. Hence, there is a need for accurate biomarkers that predict 
who will respond to chemotherapy, and to which regimen. 
 
S1314 and COXEN: S1314 is a North American Intergroup trial opening nation-wide that 
is led by the Southwest Oncology Group (SWOG), the NCI-designated cooperative group in 
which USC plays a key role (Figure 2). S1314 will enroll 184 patients with locally-advanced (T2-
T4) bladder cancer who will be randomized to one of two neoadjuvant chemotherapy regimens, 
followed by radical cystectomy. At enrollment, all patients will undergo tumor biopsy for mRNA 
extraction. The primary goal of S1314 is to analyze tumor mRNA using a novel predictive tool: 
COXEN (CO-eXpression ExtrapolatioN). COXEN begins by using the NCI-60 panel of cancer cell 
lines and tumor archives to establish unique gene expression profiles highly correlated with 
response to various chemotherapeutic agents; then, patient tumors are analyzed for presence 
or absence of those same expression profiles to predict response to various chemotherapy 
regimens. (5,6,7,8) The primary endpoint of S1314 will be whether the COXEN gene expression 
profiles generated from tumor biopsies are predictive of response to neoadjuvant therapy, 
defined as T0 (no viable tumor) at cystectomy.  
 
 

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S1314 
 
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Using these capabilities, we have collected thousands of CTC samples in multiple clinical trials in 
prostate and bladder cancer, including 2 R01- funded translational science projects embedded in 
phase III SWOG studies where we demonstrated the prognostic value of CTC analysis. (11,12) 
Although enumeration and DNA analysis of CTCs has advanced rapidly, gene expression profiling 
has lagged far behind, hampered by the persistence of contaminating background white blood 
cells (WBC) in enriched CTC samples. Our group has nonetheless pursued the goals of CTC 
expression profiling using a motorized micromanipulator pipette custom-designed in our 
laboratory for this purpose. Using this device, we successfully recovered ultra-pure CTCs 
(upCTCs) with 0 WBC contamination from human and mouse blood samples. mRNA from these 
rare cells was successfully amplified and analyzed using several new methodologies that we 
optimized in direct collaboration with the R&D teams of their manufacturers, such as highly-
multiplexed (624 gene) qPCR on the Open Array platform (Life Tech), and WTA kits (Nugen) for 
Affymetrix chip analysis or for RNAseq (see examples in Figure 4). Most recently, our laboratory 
has procured a CTC isolation platform engineered specifically for rapid, robust recovery of ultra- 
pure cells: The DepArray (Silicon Biosystems – see link) uses dielectrophoretic “cages” to trap 
and manipulate single cells, allowing selection of ultra-pure cells for recovery based on their 
immunofluorescent (IF) staining pattern in up to 6 IF channels. (13) Thus, the DEPArray platform 
offers a much more rapid, robust, and precise capability for recovering upCTCs, which then can 
be lysed for total RNA recovery, amplification, and analysis as described above. 
 
 

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Determination of COXEN score for each sample based on Affymetrix array gene expression: 
 
The COXEN workflow was developed and published by Dr. Jay Lee (U Virginia) and studied 
extensively in bladder cancer by Dr. Dan Gustafson (Colorado State) in collaboration with Drs. 
Thomas Flaig and Dan Theodorescu (U Colorado, SWOG), who serve as collaborators for this 
proposal (see letter of support from Dr. Gustafson). (14,15,16,17) Briefly, the COXEN algorithm 
may be divided into 6 distinct steps. The first of these 3 steps have already been accomplished 
in the lead-in studies to S1314 (Table 1), yielding the coefficients and probe sets to be used 
to calculate single-drug and combination-drug COXEN scores in our study. 
 
• 
Step 1 (done): Determine drug’s activity in discovery/validation bladder cancer cohorts (cell 
lines, tumors) 
• 
Step 2 (done): Measure gene expression (Affymetrix array) of discovery/validation bladder 
cancer cohorts 
• 
Step 3 (done): Select a subset of gene probes that most accurately predicts the drug’s 
activity in the discovery/validation bladder cancer cohorts 
 
 
 

 
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Using the probe sets and correlation coefficients already derived in Steps 1-3 (Table 1), new 
COXEN scores can now be calculated in our proposed study for each upCTC sample in Steps 4-6 
as follows: 
• 
Step 4: Measure gene expression in upCTC samples in the new study cohort (S1314) 
• 
Step 5: Of the gene probes selected in Step 3, identify a subset that shows a strong 
pattern of coexpression extrapolation between the discovery/validation bladder cancer 
cohorts and our new study cohort (S1314). 
• 
Step 6: Use a multivariate algorithm to predict single drug and combination drug activity 
in S1314 samples on the basis of the drugs’ activity patterns in the discovery/validation 
bladder cancer cohort and the gene probe subset selected in step 5. The output of the 
multivariate analysis is a COXEN score. 
 
Isolation of upCTCs, mRNA recovery and amplification from upCTCs, and processing of 
Affymetrix arrays will be done at USC Norris (Goldkorn Lab and CHLA Genomics Core). The 
array data then will be analyzed collaboratively with the laboratory of Dr. Daniel Gustafson (see 
Gustafson letter of support) and with Dr. Cathy Tangen at SWOG Statistics and Data Management 
Center (see SWOG letter of support) using the algorithms described above. The upCTC-derived 
single drug and combination drug COXEN scores will be analyzed for association with 
chemotherapy response (T0) and with tumor-derived COXEN gene expression, as well as for 
changes before and after chemotherapy. 
 
 
CTC REFERENCES 
1  
Ochoa A, Choi W, Su X, et al. Specific micro-RNA expression patterns distinguish the basal and 
luminal subtypes of muscle-invasive bladder cancer. (Oncotarget, in press) 
 
2  
Siegel R, Ma J, Zou Z, et al. Cancer statistics 2014. CA Cancer J Clin 64(1):9-29, 2014. 
 
3  
Stenzl A, Cowan NC, De Santis M, et al. The updated EAU guidelines on muscle-invasive and 
metastatic bladder cancer. Eur Urol  55(4):815-25, 2009. 
 
4  
Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy 
compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med  349(9):859-
66, 2003. 
 
5  
Williams PD, Cheon S, Havaleshko DM, et al. Concordant gene expression signatures predict 
clinical outcomes of cancer patients undergoing systemic therapy. Cancer Res 69:8302-9, 2009. 
 
 
 
 

 
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6  
Smith SC, Baras AS, Lee JK, et al. The COXEN principle: translating signatures of in vitro 
chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. Cancer Res 
70:1753-8, 2010. 
 
7  
Takata R, Katagiri T, Kanehira M, et al. Predicting response to methotrexate, vinblastine, 
doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide 
gene expression profiling. Clin Cancer Res 11:2625-36, 2005. 
 
8  
Smith S, Baras A, Dancik G, et al. A 20-gene model for molecular nodal staging of bladder cancer: 
development and prospective assessment. Lancet Oncol 12:137-43, 2011. 
 
9  
Hu B, Fish H and Goldkorn A. Circulating tumor cells in prostate cancer. Cancers 5(4):1676-90, 
2013. 
 
10  
Xu T, Lu B, Tai YC and Goldkorn A. A cancer detection platform which measures telomerase activity 
from live circulating tumor cells captured on microfilter. Cancer Research 70(16): 6420-6426, 2010. 
 
11  
Goldkorn A, Ely B, Quinn DI, Tangen CM, et al. Circulating tumor cell (CTC) counts are prognostic 
of overall survival (OS) in SWOG S0421-docetaxel with or without atrasentan for metastatic 
castration resistant prostate cancer (mCRPC). J Clinical Oncology 32(11):1136-42, 2014. 
 
12  
Goldkorn A, Ely B, Tangen CM, Tai YC, et al. Circulating tumor cell telomerase activity as a 
prognostic marker for overall survival in metastatic castration resistant prostate cancer: results from 
SWOG 0421. Int J of Cancer 2014 [Epub Sep 2014] 
 
13  
Hodgkinson CL, Morrow CJ, Li Y, et al. Tumorigenicity and genetic profiling of circulating tumor cells 
in small-cell lung cancer. Nature Medicine 20:897-903, 2014. 
 
14  
Williams PD, Cheon S, Havaleshko DM, et al. Concordant gene expression signatures predict 
clinical outcomes of cancer patients undergoing systemic therapy. Cancer Res 69:8302-9, 2009. 
 
15  
Smith SC, Baras AS, Lee JK, et al. The COXEN principle: translating signatures of in vitro 
chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. Cancer Res 
70:1753-8, 2010. 
 
16  
Takata R, Katagiri T, Kanehira M, et al. Predicting response to methotrexate, vinblastine, 
doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide 
gene expression profiling. Clin Cancer Res 11:2625-36, 2005. 
 
17  
Smith S, Baras A, Dancik G, et al. A 20-gene model for molecular nodal staging of bladder cancer: 
development and prospective assessment. Lancet Oncol 12:137-43, 2011. 
 
 
 
 
 
 

 
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18.3c 
 Cisplatin Germline Pharmacogenomics  
 
Objectives 
 
1. 
To assess the association of single nucleotide polymorphisms (SNP), selected for cisplatin 
sensitivity, and complete pathologic response (pT0) in muscle invasive bladder cancer after 
cisplatin-based neoadjuvant chemotherapy.  
 
2. 
To assess the association of single nucleotide polymorphisms (SNP), selected for cisplatin 
sensitivity, and pathologic response (downstaging to <pT2) in muscle invasive bladder 
cancer after cisplatin-based neoadjuvant chemotherapy.  
 
3. 
To evaluate these SNP associations, individually and in combination, with RFS and OS.  
 
4. 
To perform exploratory genome-wide analysis for platinum susceptibility germline 
polymorphisms associating with pathologic response after neoadjuvant cisplatin-based 
combination chemotherapy.   
 
5. 
To explore whether candidate SNPs are associated with chemotherapy-related adverse 
events in the neoadjuvant setting. 
 
Primary endpoint 
 
Pathologic stage at cystectomy  
 
Secondary endpoints 
 
Recurrence-Free Survival 
Overall Survival  
 
Genomic DNA will be extracted using standard protocols by Nationwide (SWOG Biorepository). All 
DNA samples will be stored until batched genotyping is conducted. Genotyping for the pre-defined 
SNPs of interest will be performed using commercially available Taqman assays. Secondary 
genome-wide association analysis will be conducted using the Illumina OmniExpress array 
(although the investigators reserve the right to use an updated platform if one is available and 
technically more advantageous). 
 
Background 
 
Cisplatin-based chemotherapy represents the only available standard therapy for locally advanced 
and metastatic urothelial cancer. Despite the fact that cisplatin-based therapy improves survival in 
these settings, only 38% of bladder cancer patients achieve a complete pathologic response to 
cisplatin in the locally advanced setting, and only 50% respond in the metastatic setting. Prediction 
of which individuals will benefit is currently not possible, but the era of genomics offers a new 
avenue for this type of pursuit.  
 
The pharmacogenomics of cisplatin has been an area of active interest, however most work has 
been conducted by searching for somatic alterations in the tumor that confer sensitivity to platinum-
based therapy. Some somatic “candidate genes”—genes known to be involved in a drug’s 
pharmacokinetic or pharmacodynamic pathways—have been recently identified (e.g., ERCC2, 
ATM, RB1, FANCC), but these are typically present only in a small subset of urothelial cancer 
patients. It is clear that these candidate genes do not entirely explain an individual’s platinum 
susceptibility, meaning that chemotherapeutic sensitivity is likely a multigenic trait. Furthermore, 
both somatic and germline alterations are likely important, and both probably act in a 
complementary fashion to determine clinical sensitivity.  

 
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Dr. O’Donnell and colleagues previously refined a genome-wide approach that permits the 
identification of multigenic chemotherapy susceptibility determinants based upon germline, rather 
than tumor DNA. Using an in vitro model which employs well-genotyped lymphoblastoid cell lines 
(LCLs) from hundreds of healthy individuals in the International HapMap Project, we treated LCLs 
with cisplatin to produce “sensitivity phenotypes”. Then, genome-wide association (GWAS) was 
performed to associate specific single nucleotide polymorphisms (SNPs). We identified a number 
of novel SNPs associated with cisplatin sensitivity in these pre-clinical models. Others have recently 
identified novel cisplatin-associated SNPs in other cancers (e.g., lung, ovarian). These SNPs 
represent novel genetic determinants of cisplatin sensitivity, identified across multiple genes or in 
regions of the genome not previously implicated. We believe that such determinants, if validated, 
could permit identification of individuals most likely to respond to cisplatin-based chemotherapy. 
 
Statistical Plan 
 
In the primary analysis, we will test 10 candidate SNPs of interest in an attempt to replicate these 
as platinum susceptibility markers for urothelial cancer. These SNPs have been selected (a) based 
upon their identification through our above-described cell-based model of platinum 
chemosensitivity, (b) based upon published demonstration of their potential utility in other cancer 
types treated with platinums (lung, ovarian, head and neck), and (c) based upon candidates 
emerging from an ongoing multi-institutional study of germline platinum susceptibility markers 
currently being conducted by the PI (O’Donnell) in collaboration with colleagues at MSKCC, Fox 
Chase Cancer Center, and supported through the Alliance for Clinical Trials in Oncology 
cooperative group.  
 
For assessment of relationship with pathologic response (both pT0 and <pT2), logistic regression 
will be conducted after adjusting for the stratification factors from the trial (T2 vs. T3, T4a and PS 
0 vs. 1), and treatment arm. To increase power, we will evaluate whether an ordinal outcome (pT0 
vs. not pT0 but <pT2 vs. no response) could be used to evaluate the association with candidate 
SNPs.  
 
Best parameterization of SNPs will be evaluated (i.e. co-dominant, recessive, log-additive), but our 
pre-specified primary analysis will code SNP (Y vs. N). Only genotypes from patients self-identified 
as Caucasian will be included in the primary (first-pass) analysis to avoid confounding by population 
stratification. Evaluation for population stratification will be conducted using a combination of self-
reported race and ethnicity to serve as a reasonable surrogate to identify genetic ancestry. All 
SNPs will be evaluated for deviation from Hardy-Weinberg.  
 
The following table assumes that there is usable DNA from 167 eligible and evaluable patients, and 
it shows the minimally detectable odds ratio for each respective response outcome that can be 
evaluated with 80% statistical power and a two-sided type I error rate of 0.05. False discovery rate 
(FDR) will be used to control the average false positive proportions among selected measures and 
will be implemented for actual reporting of results. Specifically, we will use methods proposed by 
Benjamini and Hochberg.  
 
There will be minimal statistical power to detect associations of SNPs or mutations with pathologic 
response when the prevalence of the SNP is low.   
 
Minimally detectable odds ratio for Associations of SNPs with Pathologic Response (assuming 
80% statistical power, 2-sided α= 0.05)  
 
Prevalence of SNP in the non-response group  
 
5% 
10% 
20%  
pT0 
4.30 
3.10 
2.59 

 
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<pT2 
4.52 
3.19 
2.55 
 
We anticipate a 33% pathologic complete response rate (pT0) and 52% will have <pT2 path 
response. If the SNP prevalence is in the range of 20%, then we will have good power to detect 
odds ratios in the range of 2.5 for pathologic response (pT0 or <pT2).  
 
Cox regression will be used to evaluate associations of SNPs with relapse-free survival and overall 
survival. With three years of accrual and three additional years of follow-up and median survival of 
approximately five years, we expect 85 total deaths in both arms to occur on this trial and so power 
will be low to evaluate moderate sized marker/OS and marker/RFS hazard ratios. For example, 
splitting a continuous marker at the median and evaluating the association of low vs. high marker 
status with survival, there will be 88% power to detect a hazard ratio of 2.0 which would be 
equivalent to detecting a median OS of 3.5 years versus 7.0 years.  
 
For a single SNP that is found to be significantly associated with outcome, we will report the 
sensitivity and specificity for each factor predicting pathologic response, and RFS and OS status 
at a specific landmark. For combinations of factors, a logistic regression model will be used to 
estimate a risk algorithm and the resulting risk score will be used as the prognostic marker. For the 
modeling of pathologic complete response, we expect approximately 70 pathologic complete 
responders (of the 167 eligible patients. That would allow roughly 7 predictors in a multivariable 
logistic regression model.  
 
It is acknowledged that RFS and OS clinical data will likely be available at a future time point 
(allowing for data maturation), while pathologic staging will be available immediately. Thus, the 
analysis of the primary endpoint will occur first, with the secondary analyses performed in a second 
stage at the time(s) when RFS and OS data are released. 
 
Finally, we may use the DNA received to consider other candidate SNPs and/or to conduct a GWAS 
to investigate other novel candidates. Analyses to identify germline SNPs that associate with 
clinically important chemotherapy-related adverse events (e.g., vascular thrombotic events [VTEs], 
nephrotoxicity) will also be conducted, with the opportunity to validate VTE-associated SNPs that 
will be discovered in the above-mentioned ongoing Alliance project. As next generation sequencing 
platforms become more cost effective, we will also consider exome or whole-genome sequencing. 
 
Data analysis performed by: 
SWOG statistical group.  
 
Specimen Information:  
 
Who will be performing testing?  
University of Chicago Genomics Facility (https://fgf.uchicago.edu/)  
 
What types of specimen(s) are to be utilized?  
Germline DNA extracted from peripheral blood sample collected as part of the primary study  
 
What amounts of specimen(s) are to be utilized?  
Germline DNA at a concentration no lower than 10ng/uL, and a sample volume no less than 
40uL.  
 
At what time points during treatment are specimens being utilized from?  
One time sample only, obtained anytime during the study  
 
Will any processing of specimens be required by the repository prior to shipment?   
n/a  

 
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Specify shipping instructions (e.g. room temp, wet or dry ice)  
Ship on dry ice for best quality;  
Attn: Peter H. O’Donnell M.D./Peter W. Faber Ph.D.  
Genomics Facility  
Knapp Center for Biomedical Discovery  
900 E. 57th St.  
Room 1230C  
Chicago, IL 60637  
 
Expected timeline of Project completion:  
Within 1 year of project completion for the primary endpoint.  
*As noted above, the secondary analyses will be dependent on the timing of the 
availability/release of RFS and OS clinical data.  
 
Disclosure of conflict of interest:  
No relevant conflicts of interest  
 
Other considerations (including plan for financial support, grant submission, etc.):  
PI (O’Donnell) has internal funding from a University of Chicago Comprehensive Cancer Center 
Auxiliary Board Award 
 
Pharmacogenomics References:  
 
O’Donnell PH. Bladder cancer pharmacogenomics: recent insights and future perspectives. 
Pharmacogenomics. 13(14):1553-6, 2012.  
 
O’Donnell PH et al. Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in 
Neoadjuvant Chemotherapy for Urothelial Cancer. Clin Genitourin Cancer. 14(6):511-17, 2016.  
 
Chang SS…O’Donnell PH et al., 12th Annual meeting of the Society of Urologic Oncology (SUO) 
bladder cancer sessions I and II summary report. Urol Oncol. 30(6):944-7, 2012.  
 
Huang RS et al., Platinum sensitivity-related germline polymorphism discovered via a cell-based 
approach and analysis of its association with outcome in ovarian cancer patients. Clin Cancer 
Res, 2011.  
 
Wu C et al., Genome-wide interrogation identifies YAP1 variants associated with survival of small-
cell lung cancer patients. Cancer Res, 2010. 
 
 
 
 

 
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18.3d 
DNA Damage Response Gene Alterations 
 
Objectives 
 
1. 
Evaluate whether DNA damage response (DDR) gene alterations are associated with 
response to cisplatin-based neoadjuvant chemotherapy (NAC). We will perform this 
analysis using two different methodologies: 
 
Correlate deleterious alterations within 9 DDR genes (ERCC2, ERCC5, ATM, ATR, 
FANCC, BRCA1, BRCA2, RECQL4, and RAD51C) with pathologic downstaging to 
<pT2N0 after cisplatin-based neoadjuvant chemotherapy (NAC) using the CLIA-certified 
Next Generation Sequencing (NGS) targeted sequencing panel MSK-IMPACT (Integrated 
Molecular Profiling of Actionable Cancer Targets).  
 
Correlate any alterations in ATM, RB1, FANCC or ERCC2 with pathologic downstaging to 
pT0N0 or <pT2N0 after cisplatin-based neoadjuvant chemotherapy (NAC) using the CLIA-
certified 592 Gene Next Gen Sequencing panel from Caris Life Sciences (Caris 592).  
 
2. 
Assess whether the presence of one or more mutations as defined in the primary 
objective is associated with overall survival and metastasis free survival.  
 
3. 
To evaluate whether the mutation – pathologic response rate association varies by 
chemotherapy treatment arm. 
 
Primary endpoint: Pathologic stage at cystectomy using two cutoffs as specified in Section 
10 definitions of the S1314 protocol. (1) <pT2N0 vs ≥pT2 or N+ (2) pT0N0 Secondary 
endpoints: Overall survival, metastasis free survival. 
 
MSK-IMPACT: DNA will be extracted from SWOG 1314 pre-treatment tumor and germline 
specimens for genomic DNA sequencing using MSK-IMPACT, a 468-gene exon capture 
next-generation sequencing (NGS) panel, to determine the association of deleterious 
alterations within 9 pre-selected genes with pathologic down-staging. Deleterious 
mutations within this subset of 9 DDR genes will also be evaluated for an association with 
long-term clinical outcomes, including overall survival and 2-year metastasis-free survival.  
 
We will perform whole exome sequencing of pre-treatment tumor and germline DNA from 
patients who exhibit pathologic down-staging at radical cystectomy but whose tumors have 
no deleterious alterations within the 9 DDR genes detected by MSK-IMPACT to identify 
novel somatic and/or germline alterations predictive of chemosensitivity. We will 
subsequently use these results to interrogate the tumors of non-responders in a targeted 
fashion to confirm that these alterations are enriched in the DDR wild-type responders.   
 
In addition, we hope to work with the SWOG investigative team to perform an integrated 
analysis of the identified genomic mutations in conjunction with mRNA and miRNA 
expression subtypes already planned or proposed.  
 
Caris 592 Gene Next Gen Sequencing panel (Caris 592):  
 
Direct sequence analysis is performed on tumor derived DNA. An Agilent custom designed 
SureSelect XT assay is used to enrich 592 whole-gene targets. The genes and amino acids 
evaluated in this report can be found at www.carislifesciences.com. All variants reported 
by this assay are detected with > 99% confidence based on the frequency of the mutation 
present and the amplicon coverage. This test is not designed to distinguish between germ 
line inheritance of a variant or acquired somatic mutation. This test has a sensitivity to 
detect as low as approximately 10 % population of cells containing a mutation with an 

 
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analytic sensitivity of 96.9% to detect variants with frequency greater than 5%. This may 
not detect insertion/deletions events that are larger than 44 bases. This test has not been 
cleared or approved by the United States Food and Drug Administration (FDA) as such 
approval is not necessary. All performance characteristics were determined by Caris Life 
Sciences. Benign and non-coding variants are not included in this report but are available 
upon request. The versioned reference identifier used for the transcript ID was Feb.2009 
(GRCh37/hg19). Total mutational load is calculated using only missense mutations that 
have not been previously reported as germline alterations. A high mutational load is a 
potential indicator of immunotherapy response (Le et al., NEJM, 2015; Rizvi et al., Science, 
2015; Rosenberg et al., Lancet, 2016; Snyder et al., NEJM, 2014). Microsatellite instability 
status by NGS (MSI-NGS) is measured by the direct analysis of known microsatellite 
regions sequenced in the NGS panel. To establish clinical thresholds, MSI-NGS results 
were compared with results from over 2,000 matching clinical cases analyzed with 
traditional, PCR-based methods. Genomic variants in the microsatellite loci are detected 
using the same depth and frequency criteria as used for mutation detection. Only insertions 
and deletions resulting in a change in the number of tandem repeats are considered in this 
assay. Some microsatellite regions with known polymorphisms or technical sequencing 
issues are excluded from the analysis. The total number of microsatellite alterations in each 
sample are counted and grouped into three categories: High, Equivocal and Stable. MSI-
Low results are reported in the Stable category. Equivocal results have a total number of 
microsatellite alterations in between High and Stable. 
 
Background 
 
Cisplatin-based NAC followed by radical cystectomy (RC) is a standard of care for the 
curative-intent treatment of MIBC. Down-staging to <pT2 (non-muscle invasive disease) is 
associated with > 85% survival at 5 years. However, prospective identification of those 
patients who derive maximal benefit from NAC remains elusive. Published findings by our 
groups reveal two separate but related mutational patterns predictive of response and 
survival. 
 
4. 
Deleterious alterations in DDR genes identified by whole exome sequencing 
(WES) and MSK-IMPACT  
 
a. 
Deleterious alterations in DDR genes, most commonly the nucleotide 
excision repair (NER) gene ERCC2, are present in 23-39% of bladder 
cancers. (1,2,3)  
 
b. 
DDR gene mutations are associated with pathologic down-staging and 
improved survival in MIBC patients treated with cisplatin-based NAC. 
(4,5,6)  
 
c. 
ATM/RB1/FANCC/ERCC2  
 
d. 
In the TCGA the rate of ERCC2 mutations was 10%, and the rate of one 
or more ATM/RB1/FANCC mutations was 38%. Therefore, we estimate 
that at least 38% of patients in the COXEN study will have one or more of 
these mutations. (7) 
 
e. 
These four specific DDR gene mutations are associated with pathologic 
down-staging and improved survival in MIBC patients treated with 
cisplatin-based NAC in both discovery and validation cohorts. (8,9,10) 
 
On the basis of these preliminary data and observations, we hypothesize that two separate 
but related genomic mutational patterns (1) deleterious DDR gene alterations within 9 
genes (MSK-IMPACT) and (2) ATM/RB1/FANCC/ERCC2 alterations (Caris 592) are 

 
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associated with pathologic down-staging after NAC, and that these alterations can identify 
patients with deep, durable outcomes. We propose to test this hypothesis using pre-
treatment samples from SWOG S1314. Pre-treatment tumor and germline DNA are 
required for analysis. This prospective trial provides an ideal opportunity to rigorously 
validate the association of these mutational patterns with pathologic down-staging in a 
retrospective-prospective fashion, and also to identify new genomic mediators of NAC 
sensitivity in those patients without the presence of these gene mutations, since 50-60% 
of patients who demonstrate down-staging after NAC lack somatic alterations in canonical 
DDR pathway genes. (11,12,13) We will also compare the rates of mutations by treatment 
arm to delineate differences in frequency and association with response that may be 
attributable to chemotherapy regimen. 
 
5. 
Rationale for separate testing using MSK-IMPACT and Caris 592  
 
We are requesting separate aliquots of DNA to test two genomic profiling 
platforms: MSK-IMPACT and Caris 592. While both methods allow for detection of 
genomic alterations, the methods used, results expected, and clinical access differ 
between platforms. 
 
MSK-IMPACT is a CLIA certified custom hybridization-capture based assay that 
sequences all exons and select introns within 468 commonly altered genes across 
cancer types. The assay utilizes tumor and matched normal sample pairs to 
interrogate the somatic (tumor-specific) genomic profile to detect single nucleotide 
variants, short insertions and deletions, copy number aberrations, and structural 
rearrangements. While the initial discovery that ERCC2 alterations were predictive 
for chemo-sensitivity used a more unbiased approach (i.e., whole exome 
sequencing, WES), the MSK-IMPACT gene panel includes ERCC2 and additional 
genes that comprise all critical DNA damage response pathways. Moreover, a 
targeted panel approach has the advantage of lower DNA input requirements (as 
low as 50-100 ng for MSK-IMPACT) and greater coverage (higher sensitivity) at 
reasonable cost compared to WES. The platform has successfully detected 
genomic alterations within DNA extracted from both frozen and paraffin-embedded 
tissue from a variety of specimen types, including biopsies, surgical resections, 
and cytology. The sequencing data from several published projects are available 
through the publicly accessible cBio portal, while access is provided to 
collaborators for ongoing projects that have yet to be published. Notably, this 
platform successfully identified deleterious DDR gene alterations within multiple 
DDR pathways in patients who responded to neoadjuvant dose dense gemcitabine 
and cisplatin in a multicenter phase II study and this finding serves as the basis for 
the 9 pre-defined genes that have been selected for further validation within this 
proposal (Iyer et al, JCO, in press). Moreover, MSK-IMPACT will be the centralized 
sequencing platform for a prospective cooperative group trial that will open to 
accrual in 2018 (A031701) in which patients with muscle-invasive bladder cancer 
will be molecularly stratified to organ preservation versus definitive local therapy 
based upon the presence or absence of deleterious alterations within 9 DDR genes 
within their pre-treatment TUR specimen, including ERCC2, ERCC5, ATM, ATR, 
FANCC, BRCA1, BRCA2, RECQL4, and RAD51C. 
 
The Caris 592 test is also panel-based but uses a curation process to make calls 
without incorporating data from the germline. Though the Caris method is slightly 
different from the FoundationOne testing that was used to discover and validate 
the ATM/RB1/FANCC mutation pattern, it is overall similar in being agnostic to the 
germline. The Caris method has the distinct advantage over the FoundationOne 
method of including ERCC2, which based on our groups’ collaborative efforts, we 
feel is critical to the accurate assessment of cisplatin sensitivity. When analyzing 
the samples from reference 2 below using the Broad WES method that, similar to 

 
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MSK-IMPACT, deletes germline mutations, the contributions of RB1, ATM and 
FANCC were lost. However, we have shown that using germline agnostic 
sequencing approaches, these alterations – most powerfully RB1 and ATM – allow 
for greater sensitivity and predictive ability. Lastly, it is important to test for these 
mutations using a method that is both CLIA-certified and commercially available to 
practicing 
clinicians 
outside 
of 
MSKCC. 
The 
4-gene 
panel 
(ATM/RB1/FANCC/ERCC2) is currently being used to assess predictive ability of 
this panel for complete response allowing for bladder preservation in an ongoing 
clinical trial at Fox Chase (NCT02710734). The disadvantage is that some aspects 
of the curation process are proprietary and thus not easily reproducible outside of 
Caris. Caris has agreed to share and allow for public deposit of all sequencing 
data/calls as part of this project. 
 
6. 
Statistical Considerations for DNA Damage Response gene alterations 
 
For genes that are common between the two platforms, we will descriptively 
compare the level of agreement (Yes vs. No) of alteration calls, but no formal test 
will be employed.  
 
For each platform (MSK-IMPACT and Caris 592), we will conduct similar analytic 
strategies. Patients found with any alteration in the panel of pre-specified genes 
will be coded as alteration=Y, otherwise patients will be coded as N. Two by two 
tables will be constructed which cross-classify alteration with pathologic response 
(down-staging or pT0 status) vs. no response. Estimates of sensitivity and 
specificity along with 95% confidence intervals will be provided. Additionally, a 
logistic regression model will be fit with stratification factors placed in the model as 
covariates along with an indicator for alteration, and we will model the outcome of 
path response. The area under the curve will be estimated, and the ROC curve will 
be generated based on the risk score from the model. Comparisons of 
categorization will also be made for prediction of path response using the model 
with only strat factors with strat factors and an indicator for presence of alterations. 
The incremental improvement between the models will be attributed to the 
contribution of alteration information. Because the list of genes and methodology 
is pre-specified, we will employ a p-value of 0.05 as the significance level  
 
In additional exploratory analyses we will examine individual gene alterations and 
downstaging and pT0 status combined and separately to see if some genes are 
driving the association with response. We will also evaluate whether having more 
than one alteration increases the odds of having a path response to platinum-
based chemotherapy. 
 
In secondary analyses, we will also adjust for treatment arm and evaluate an 
alteration by treatment arm interaction term to see if the alteration – path response 
association varies by treatment arm. The statistical power for this test will be very 
low, and results will focus on descriptive statistics.  
 
We estimate that 160 patients from S1314 will be eligible for this TM substudy by 
being eligible for the clinical trial, having TURBT tissue and blood available, 
received at least 3 cycles of neoadjuvant chemotherapy or progressed on chemo, 
and are assessable for pathologic response at time of cystectomy. This number 
also allows for a small fraction of assay failures. We further assume that the path 
response rate in those without an alteration is either 15% (top half of table) or 25% 
(lower half of table). We specify a two-sided alpha of 0.05 and report minimally 
detectable response rate differences that can be observed with at least 80% 
power. We are not adjusting for multiple testing because the finite number. 
 

 
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Minimally Detectable Odds Ratios for Gene Alteration and Pathologic Response ( 
downgrading or pT0) n=160 Patients Gene Alteration (Y/N) Frequency  
15%  
20%  
30%  
40%  
 
Assume 15% path response in those without alteration  
Path response 
difference (w/o 
vs. w/)  
15% vs. 44%  
15% vs. 41%  
15% vs. 37%  
15% vs. 36%  
 
Assume 25% path response in those without alteration  
Path response 
difference (w/o 
vs. w/)  
25% vs. 57%  
25% vs. 53%  
25% vs. 50%  
25% vs. 48%  
 
Based on prior MSK-IMPACT analyses that showed that 885 of patients bearing 
an alteration of interest had a pathologic response and only 15% response for 
those without an alteration, our sample of 160 patients should provide good power 
to detect response rates differences similar to those that have been observed 
previously.  
 
Additional analyses looking at gene alteration and its association with metastasis-
free survival and overall survival will use a Cox regression model adjusting for 
stratification factors, treatment arm and evaluating the hazard ratio for alteration 
status (Y/N). Patients will be censored at their last contact date. We anticipate 
these outcome data will be available 1-2 years after the pathologic response data 
have been analyzed. In order to evaluate sensitivity and specificity we will select a 
landmark timepoint for events occurring prior to 3 years (Y/N) and we will generate 
ROC curves and calculate the AUC. 
 
Data analysis performed by:  
 
MSK-IMPACT sequencing calls performed by MSKCC Center for Molecular Oncology and 
annotated by Dr. Gopa Iyer.  
Caris 592 sequencing calls performed by CARIS per their commercial platform.  
Raw data and calls made using both methods will be available to investigators within SWOG and 
publicly deposited as per journal requirements.  
• 
Statistical analysis by S1314 SWOG Statistical Team  
 
Specimen Information:  
 
Who will be performing testing? (Please provide complete laboratory and contact information.)  
Gopa Iyer, M.D.  
Memorial Sloan Kettering Cancer Center  
Mortimer B. Zuckerman Research Center (ZRC)  
417 East 68th Street  
8th floor—Room ZRC-827  
New York, NY 10065  
T: 646-888-2649 (Lab)  
646-888-4737 (Office)  
 
Caris Life Sciences 
Translational Medicine Study Proposal Form (updated 3/14) p. 6 Attachment 1  
4610 South 44th Place, Suite 100  
Phoenix, Arizona 85040  
 
 

 
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What types of specimen(s) are to be utilized?  
  
Peripheral blood will be utilized for germline DNA extraction and sequencing.  
DNA from tumor tissue (previously extracted through SWOG) will be used for tumor tissue 
sequencing.  
 
What amounts of specimen(s) are to be utilized?  
 
DNA has already been extracted from the TURBT pre-treatment tumor samples.  
• 
For MSK-IMPACT a minimum of 250 ng of tumor and 200 ng of germline DNA will be 
required.  
• 
For Caris 592, 250 ng of tumor DNA is preferred. A minimum of 100 ng is required.  
 
All DNA should be shipped in dry ice. At the end of the study, any remaining DNA will be returned 
to the SWOG biorepository.  
 
At what time points during treatment are specimens being utilized from?  
 
Only pre-treatment TURBT or biopsy and peripheral blood specimens are required.  
 
Will any processing of specimens be required by the repository prior to shipment?   
 
No 
 
Specify shipping instructions  
Blood should be shipped in dry ice.  
Germline or somatic DNA should be shipped in dry ice.  
 
Expected timeline of Project completion:  
1 year  
 
Disclosure of conflict of interest:  
 
MSK patent for predicting platinum sensitivity  
FCCC patent for predicting platinum sensitivity 
 
 
DNA Damage Response Gene Alterations References 
1  
Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 Mutations 
Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma. Cancer Discov. 
4(10):1140-53, 2014. 
 
2  
Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG, et al. Defects in DNA 
repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive 
bladder cancer. Eur Urol. 68(6):959-67, 2015. 
 
3  
Liu D, Plimack ER, Hoffman-Censits J, Garraway LA, Bellmunt J, Van Allen E, et al. Clinical 
validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder 
carcinoma. JAMA oncology. 2(8):1094-6, 2016. 
 
 
 

 
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4  
Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 Mutations 
Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma. Cancer Discov. 
4(10):1140-53, 2014. 
 
5  
Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG, et al. Defects in DNA 
repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive 
bladder cancer. Eur Urol. 68(6):959-67, 2015. 
 
6  
Liu D, Plimack ER, Hoffman-Censits J, Garraway LA, Bellmunt J, Van Allen E, et al. Clinical 
validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder 
carcinoma. JAMA oncology. 2(8):1094-6, 2016. 
 
7  
Lotan Y, Woldu SL, Sanli O, Black P, Milowsky MI. Modelling cost-effectiveness of a biomarker-
based approach to neoadjuvant chemotherapy for muscle-invasive bladder cancer. BJU Int. Epub 
ahead of print (PMID: 29603871), 2018. 
 
8  
Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 Mutations 
Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma. Cancer Discov. 
4(10):1140-53, 2014. 
 
9  
Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG, et al. Defects in DNA 
repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive 
bladder cancer. Eur Urol. 68(6):959-67, 2015. 
 
10  
Liu D, Plimack ER, Hoffman-Censits J, Garraway LA, Bellmunt J, Van Allen E, et al. Clinical 
validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder 
carcinoma. JAMA oncology. 2(8):1094-6, 2016. 
 
11  
Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 Mutations 
Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma. Cancer Discov. 
4(10):1140-53, 2014. 
 
12  
Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG, et al. Defects in DNA 
repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive 
bladder cancer. Eur Urol. 68(6):959-67, 2015 
 
13  
Liu D, Plimack ER, Hoffman-Censits J, Garraway LA, Bellmunt J, Van Allen E, et al. Clinical 
validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder 
carcinoma. JAMA oncology. 2(8):1094-6, 2016. 
 
 
 
 
 
 
 

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S1314 
 
Page 1 
 
Version Date: 7/15/19 
 
 
 
Informed Consent Model for  S1314 
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:  
 
This model informed consent form has been reviewed by the DCTD/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed.  (Institutions 
should attempt to use sections of this document that are in bold type in their entirety.)  Editorial 
changes to these sections may be made as long as they do not change information or intent.  If 
the institutional IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they may be justified in writing by the investigator and approved by the 
IRB.  Under these circumstances, the revised language, justification and a copy of the IRB 
minutes must be forwarded to the SWOG Operations Office for approval before a patient may be 
registered to this study.   
 
Please particularly note that the questions related to banking of specimens for future study 
are in bolded type and may not be changed in any way without prior approval from the 
SWOG Operations Office. 
Readability Statistics:   
 
Flesch Reading Ease  
61.7 (targeted above 55) 
Flesch-Kincaid Grade Level 8.6 (targeted below 8.5) 
 
• 
Instructions and examples for informed consent authors are in [italics].  
• 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
• 
The term "study doctor" has been used throughout the model because the local 
investigator for a cancer treatment trial is a physician.   If this model is used for a 
trial in which the local investigator is not a physician, another appropriate term 
should be used instead of "study doctor".  
• 
The dates of protocol updates in the header and in the text of the consent is for 
reference to this model only and should not be included in the informed consent 
form given to the prospective research participant.  
• 
The local informed consent must state which parties may inspect the research 
records. This includes the NCI, the drug manufacturer for investigational studies, 
any companies or grantors that are providing study support (these will be listed in 
the protocol's model informed consent form) and SWOG.  
 
"SWOG" must be listed as one of the parties that may inspect the research records 
in all protocol consent forms for which patient registration is being credited to 
SWOG.  This includes consent forms for studies where all patients are registered 
directly through the SWOG Data Operations Office, all intergroup studies for 
which the registration is being credited to SWOG (whether the registration is 
through the SWOG Data Operations Office or directly through the other group), as 
well as consent forms for studies where patients are registered via CTSU and the 
registration is credited to SWOG. 

 
S1314 
 
Page 2 
 
Version Date: 7/15/19 
 
 
 
• 
When changes to the protocol require revision of the informed consent document, 
the IRB should have a system that identifies the revised consent document, in order 
to preclude continued use of the older version and to identify file copies.  An 
appropriate method to identify the current version of the consent is for the IRB to 
stamp the final copy of the consent document with the approval date.  The stamped 
consent document is then photocopied for use.  Other systems of identifying the 
current version of the consent such as adding a version or approval date are allowed 
as long as it is possible to determine during an audit that the patient signed the most 
current version of the consent form.  
 
*NOTES FOR LOCAL INVESTIGATORS:  
• 
The goal of the informed consent process is to provide people with sufficient 
information for making informed choices.   The informed consent form provides a 
summary of the clinical study and the individual's rights as a research participant.  
It serves as a starting point for the necessary exchange of information between the 
investigator and potential research participant.  This model for the informed consent 
form is only one part of the larger process of informed consent. For more 
information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared 
by the Comprehensive Working Group on Informed Consent in Cancer Clinical 
Trials for the National Cancer Institute.  The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/ 
• 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
• 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is 
available for your patients.  The pamphlet is titled: "Taking Part in Cancer 
Treatment Research Studies".  This pamphlet may be ordered on the NCI Web site 
at https://cissecure.nci.nih.gov/ncipubs or call 1-800-4- CANCER (1-800-422-
6237) to request a free copy.  
• 
Optional feature for Local Investigators: Reference and attach drug sheets, 
pharmaceutical information for the public, or other material on risks.  Check with 
your local IRB regarding review of additional materials. 
 
*These notes for authors and investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant.  

 
S1314 
 
Page 3 
 
Version Date: 7/15/19 
 
 
 
Study Title for Study Participants: Testing the use of the co-expression 
extrapolation (COXEN) program to predict response to usual chemotherapy 
in patients with localized, muscle invasive bladder cancer 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
S1314, “A Randomized Phase II Study of Co-Expression Extrapolation 
(COXEN) With Neoadjuvant Chemotherapy for Localized, Muscle-Invasive 
Bladder Cancer” 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.  Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
 
What is the usual approach to my muscle-invasive bladder cancer? (updated 
5/22/15) 
 
You are being asked to take part in this study because you have muscle invasive bladder 
cancer. People who are not in a study are usually treated with neoadjuvant therapy, which 
involves a combination of chemotherapy drugs followed by surgery.  Radiation therapy 
with chemotherapy or surgery alone are other treatment options.  In this study, tests on 
your bladder biopsy sample will be used to see if it can predict your response to 
chemotherapy.  You will be randomized between a combination of gemcitabine, cisplatin, 
or a different combination of methotrexate, vinblastine, doxorubicin, cisplatin, and 
filgrastim (or pegfilgrastim) which will be used before surgery.   These are both standard 
treatment combinations for bladder cancer and may be given even if you are not in this 
study.   
 
What are my other choices if I do not take part in this study? 
 
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above without being in a 
study 
• you may choose to take part in a different study, if one is available 
• or you may choose not to be treated for cancer but you may want to receive 
comfort care, also called palliative care, to relieve symptoms. This type of care 
helps reduce pain, tiredness, appetite problems, and other problems caused by 
the cancer.  It does not treat the cancer directly, but instead tries to improve how 
you feel.  Comfort care tries to keep you as active and comfortable as possible. 

 
S1314 
 
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Why is this study being done? 
 
The primary focus of this study is to see if looking at tumor biomarkers using a program 
called “coexpression extrapolation or COXEN” may predict your response to 
chemotherapy before surgery.  The COXEN program will not select your therapy, but the 
type of chemotherapy that you receive will be randomly decided. Information will be 
gathered and after you complete your participation in the study, researchers will look at 
this information and outcomes for all study participants to see how COXEN relates to how 
participants responded to chemotherapy.   Other potential tests to predict a patient’s 
response to chemotherapy will also be evaluated.  In this study, you will receive the 
treatment in Arm 1 (gemcitabine and cisplatin) or the treatment in Arm 2 [methotrexate, 
vinblastine, doxorubicin, cisplatin, and filgrastim (or pegfilgrastim).  There will be about 
230 people taking part in this study (115 in each arm). 
 
What are the study groups? 
 
A computer will randomly put you in either of two treatment groups (Arm 1 or Arm 2). This is 
done because no one knows if one type of chemotherapy is better, the same, or worse than the 
other type of chemotherapy. Once you are put in one group, you cannot switch to the other 
group. Neither you nor your doctor can choose which group you will be in. 
 
Patients in Arm 1 will receive the combination chemotherapy gemcitabine, cisplatin, and 
possibly filgrastim (or pegfilgrastim).  All of the drugs will be delivered into your vein with the 
exception of filgrastim (or pegfilgrastim) which will be given as a shot in the fatty layer of tissue 
just under the skin.  On Day 1, you will receive gemcitabine and cisplatin.  On Day 8, you will 
only receive the gemcitabine, possibly followed by a single dose of pegfilgrastim 24-48 hours 
after the completion of chemotherapy for each cycle or alternatively filgrastim on Days 9-13.  In 
some cases, you will not receive either filgrastim or pegfilgrastim based on the assessment of 
your treating medical provider.  The drugs will be given to you again every 21 days for a total of 
4 cycles.  (Each 21-day period is called a “cycle”.) You will have a physical exam and blood 
tests done at the beginning of each cycle.  A CT scan or MRI (of the abdomen and pelvis) and a 
CT scan or x-ray (of the chest) will be done after 4 cycles of treatment.     
 
Patients in Arm 2 will receive the combination chemotherapy methotrexate, vinblastine, 
doxorubicin, cisplatin, and filgrastim (or pegfilgrastim).  All of the drugs will be delivered into 
your vein with the exception of filgrastim (or pegfilgrastim) which will be given as a shot in the 
fatty later of tissue just under the skin.   On Day 1, you will receive methotrexate.  On Day 1 (or 
Day 2) you will receive the vinblastine, doxorubicin, and cisplatin.  On Days 3-7 (or Days 2-6, if 
all the chemotherapy was given on Day 1), you will receive the filgrastim; alternatively, you may 
receive a single dose of pegfilgrastim 24-48 hours after the completion of chemotherapy for each 
cycle.  The drugs will be given to you again every 14 days for a total of 4 cycles.  (Each 14-day 
period is called a “cycle”.) You will have a physical exam and blood tests done at the beginning 
of each cycle.  A CT scan or MRI (of the abdomen and pelvis) and a CT scan or x-ray (of the 
chest) will be done after 4 cycles of treatment.     

 
S1314 
 
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Version Date: 7/15/19 
 
 
 
Patients in both arms will undergo a standard lymph node and bladder removal within 70 days 
after completing chemotherapy.  
 
How long will I be in this study? 
 
You will receive the study drugs for 4 cycles of treatment or as long as your disease does not get 
worse and the side effects are not too severe. After you finish the study drugs, your doctor will 
continue to watch you for side effects and follow your condition for up to five years. 
 
What extra tests and procedures will I have if I take part in this study?  
 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer.  However, there are some extra exams and tests that you will need to have if you take 
part in this study. 
 
Small pieces of cancer tissue removed by a previous surgery or biopsy will be collected before 
you begin the study and tested using the COXEN program.  In addition, a small amount of your 
blood (about 3 teaspoons) and urine (about 8 teaspoons) will be collected before you begin the 
study for study related tests.  Prior to surgery, an additional urine collection (about 8 teaspoons) 
will be done and saved for additional study.  If any cancer remains at the time of surgery, a small 
sample of cancer tissue will be taken for the study as well.  All of these specimens will be sent to 
a central laboratory for testing.  These samples are required in order for you to take part in this 
study because the research on the samples will be analyzed to look for biologic markers to learn 
about bladder cancer and also to study ways to predict who will respond to chemotherapy.   
 
Neither you nor your health care plan/insurance carrier will be billed for the collection of the 
samples that will be used for this study. You and your study doctor will not receive the results of 
any tests done on your samples. 
 
What possible risks can I expect from taking part in this study?  
 
If you choose to take part in this study, there is a risk that you may: 
• Lose time at work or home and spend more time in the hospital or doctor’s office 
than usual 
• Be asked sensitive or private questions which you normally do not discuss 
 
The drugs 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 be testing your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 

 
S1314 
 
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• Some side effects may go away soon, some may last a long time, or some may never 
go away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of 
a problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you 
are having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers 
know about. There might be other side effects that researchers do not yet know about. If 
important new side effects are found, the study doctor will discuss these with you. 
 
Arm 1 - Possible side effects of gemcitabine, cisplatin, and pegfilgrastim may include the 
following:   
 
COMMON, SOME MAY BE SERIOUS 
More than 20 out of 100 people receiving gemcitabine, cisplatin, and pegfilgrastim may have: 
• Low white blood cell counts (may make you more likely to get an infection) 
• Low red blood cell counts (may make you feel tired or weak) 
• Low platelet counts (may make you more likely to bruise or bleed) 
• Nausea 
• Vomiting 
• Loss of appetite 
• Diarrhea 
• Fatigue 
• Blood measurements of kidney function (creatinine) and normal elements in the blood 
including blood sugar (glucose), potassium, magnesium, calcium, and sodium may 
become abnormal   
• Lightheadedness 
• Headaches 
• Changes in blood pressure 
• Skin irritation at site of drug injection 
• Damage to kidneys 
• Damage to hearing 
• Rash 
• Flu-like illness with fever on day of chemotherapy 
• Electrolytes, which are normal elements measured in the blood, including potassium, 
magnesium, and sodium may become low and possibly require replacement 
• Bone pain 
 

 
S1314 
 
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OCCASIONAL, SOME MAY BE SERIOUS 
About 4 to 20 out of 100 people receiving gemcitabine, cisplatin, and pegfilgrastim may have: 
• Sores in mouth and/or throat 
• Alterations in taste 
• Allergic reaction (including flushing, skin rash, changes in blood pressure and/or 
difficulty breathing) 
• Stomach cramps 
• Hair loss 
• Numbness in the hands and feet 
• Loss of blood supply to the intestines that may require surgery 
• Inflamed pancreas 
• Dizziness and shooting back pain when bending your neck forward 
• Confusion 
• Blurred vision or a sensation of flashing light 
• Mood changes 
• Liver damage and/or failure 
• Seizures 
• Fainting 
• Irregular heartbeat 
• Heart attack  
• Ringing in the ears 
• High frequency hearing loss – This can be permanent 
 
 
RARE, AND SERIOUS 
About 3 or fewer out of 100 people receiving gemcitabine, cisplatin, and pegfilgrastim may 
have: 
• Cancer of the bone marrow caused by chemotherapy later in life. 
• Seizure 
 

 
S1314 
 
Page 8 
 
Version Date: 7/15/19 
 
 
 
Arm 2 - Possible side effects of methotrexate, vinblastine, doxorubicin, cisplatin, and 
filgrastim (or pegfilgrastim) may include the following:   
 
 
 
COMMON, SOME MAY BE SERIOUS 
More than 20 out of 100 people receiving methotrexate, vinblastine, doxorubicin, cisplatin, and 
filgrastim (or pegfilgrastim) may have: 
• Low number of red blood cells (anemia) - This can lead to shortness of breath, 
weakness, and fatigue.  
• Low number of platelets which help the blood clot – This can lead to unexplained 
bruising or bleeding. 
• Low number of white blood cells – This can make you more vulnerable to 
infection.  
• Hair loss 
• Nausea 
• Vomiting 
• Skin irritation at site of drug injection which can be severe  
• Damage to kidneys 
• Damage to hearing 
• Changes in urine color (doxorubicin may discolor your urine for up to 1-2 days but 
this is harmless) 
• Soreness or painful ulcers of the mouth lasting a couple of days 
• Sensitivity to the sun  
• Blood measurements of kidney function (creatinine) and normal elements in the 
blood including blood sugar (glucose), potassium, magnesium, calcium, and 
sodium may become abnormal   
• Electrolytes, which are normal elements measured in the blood, including 
potassium, magnesium, and sodium may become low and possibly require 
replacement 
• Sores in mouth and/or throat 
• Bone pain 

 
S1314 
 
Page 9 
 
Version Date: 7/15/19 
 
 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
About 4 to 20 out of 100 people receiving methotrexate, vinblastine, doxorubicin, cisplatin, and 
filgrastim (or pegfilgrastim) may have: 
• Allergic reaction 
• Upset bowels – this can lead to either constipation or diarrhea 
• Loss of appetite 
• Weight loss 
• Strange taste - A metallic or bitter taste can occur during treatment.  A flavored hard 
candy or mint will help to disguise this taste. 
• Flu-like symptoms (such as fever, aches, pains, and shivering) 
• Tingling and numbness in the fingers or toes 
• Ringing in the ears 
• High frequency hearing loss – This can be permanent 
• Skin and nail changes 
• Rash or irritation at the injection site 
• Weakness of the heart – This is uncommon and can happen with increasing doses of 
doxorubicin. 
 
RARE, AND SERIOUS 
About 3 or fewer out of 100 people receiving methotrexate, vinblastine, doxorubicin, cisplatin, 
and filgrastim (or pegfilgrastim) may have: 
• Sore eyes 
• Depression 
• Headaches 
• Jaw pain 
• Seizure 
• Cancer of the bone marrow caused by chemotherapy later in life. 
• Death – In rare cases, death can occur in patients with a severe allergic reaction to the 
chemotherapy or in patients who develop a life-threatening infection. 
 
Let your study doctor know of any questions you have about possible side effects. You can 
ask the study doctor questions about side effects at any time. 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this 
study. The drugs used in this study could be very damaging to an unborn baby. Birth 
control measures should be continued for at least 6 months after the completion of 
chemotherapy and until your study doctor indicates it is acceptable to stop. Check with the 
study doctor about what types of birth control or pregnancy prevention to use while in this 
study. 

 
S1314 
 
Page 10 
 
Version Date: 7/15/19 
 
 
 
 
What possible benefits can I expect from taking part in this study?  
 
This study is designed to test the COXEN program and its ability to predict responses to 
chemotherapy.  It is not possible to know at this time if the COXEN program will be able to 
accurately predict responses to chemotherapy. This study will help researchers learn things 
that will help people in the future. 
 
Can I stop taking part in this study? 
 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
 
The 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. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB or FDA 
 
What are my rights in this study? 
 
 Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 
at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.) 
 
What are the costs of taking part in this study?  
 
You and/or your health plan/insurance company will need to pay for all of the other costs of 
treating your cancer while in this study, including the cost of managing any side effects. Before 
you decide to be in the study, you should check with your health plan or insurance company to 
find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 

 
S1314 
 
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What happens if I am injured or hurt because I took part in this study?  
 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for 
injury.  Your insurance company may not be willing to pay for study-related injury.  If you have 
no insurance, you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
Who will see my medical information?  
 
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you.  Some of your health information, and information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
• SWOG 
• Your local Institutional Review Board, IRB, is a group of people who review the research 
with the goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., and 
similar ones if other countries are involved in the study. 
• The Cancer Trials Support Unit (CTSU), a research group sponsored by the National 
Cancer Institute (NCI) to provide greater access to cancer trials. 
 
 [Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
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 

 
S1314 
 
Page 12 
 
Version Date: 7/15/19 
 
 
 
most, the Web site will include a summary of the results.  You can search this Web site at 
any time. 
 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation 
found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The 
text in this paragraph cannot be revised.] 
 
Who can answer my questions about this study? 
 
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). 
 
NOTE:  Use the following types of format only when the "additional studies" are optional for the 
patient.  When mandatory, the description should be imbedded as a part of the study description 
in the main consent. 
 
ADDITIONAL STUDIES SECTION: 
 
This part of the consent form is about optional studies that you can choose to take part in. You 
will not get health benefits from any of these studies. The researchers leading this optional study 
hope the results will help other people with cancer in the future. 
 
The results will not be added to your medical records, nor will you or your study doctor know 
the results. 
 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say ‘no’ to any or all of these studies. If you sign up for but cannot complete any of the 
studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
1. 
Future Contact 
I agree to allow my study doctor, or someone approved by my study doctor, to 
contact me regarding future research involving my participation in this study.  
Yes 
No 
 
2. 
Optional Blood Collection for Ultra-Pure Circulating Tumor Cells 
(upCTC)  
 
In an effort to determine if there are some patients who are more or less likely to benefit from the 
combination of gemcitabine and cisplatin versus the combination of methotrexate, vinblastine, 
doxorubicin, cisplatin and filgrastim (or pegfilgrastim), two tubes of your blood will be collected 

 
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before you start treatment and before Cycle 2. If you agree to participate in this study, your blood 
will be studied for the presence of cancer cells that are shed by your tumors into your blood 
stream. DNA and RNA from these circulating tumor cells (CTCs) will be analyzed to better 
understand which cancers respond to chemotherapy. This blood will also be studied for DNA not 
found in cells but that is also present in your blood because it has been released from the cancer 
in your body.  
 
Blood Sample for upCTC: 
 
I agree to participate in the upCTC study and have two additional blood samples collected 
and submitted. 
 
Yes 
No 
 
3.  
Optional Biobanking for Possible Future Studies 
 
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of 
this research is done using samples from your tissue, blood, urine, or other fluids. Through these 
studies, researchers hope to find new ways to prevent, detect, treat, or cure health problems. 
 
Some of these studies may be about genes. Genes carry information about features that are found 
in you and in people who are related to you. Researchers are interested in the way that genes 
affect how your body responds to treatment. 
 
 
If you choose to take part in the main study, a sample of tissue from your previous biopsy and 
blood and urine samples will be collected prior to starting on protocol treatment. The researchers 
ask your permission to store and use your leftover samples from the planned research and health 
information for medical research. The research that may be done is unknown at this time. Storing 
samples for future studies is called “biobanking”. The Biobank is being run by SWOG and 
supported by the National Cancer Institute. 
 
WHAT IS INVOLVED? 
 
If you agree to allow your specimens to be stored and used in future research, here is what will 
happen next: 
1) Your specimens will be collected as described above and will be sent to the Biobank.  
2) Your specimens and some related information may be stored in the Biobank, along 
with samples and information from other people who take part. The specimens will be 
kept until they are used up. 
3) Qualified researchers can submit a request to use the materials stored in the Biobanks. 
A science committee at the clinical trials organization, and/or the National Cancer 
Institute, will review each request. There will also be an ethics review to ensure that 
the request is necessary and proper. Researchers will not be given your name or any 
other information that could directly identify you.  

 
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4) Neither you nor your study doctor will be notified when research will be conducted or 
given reports or other information about any research that is done using your samples.  
5) Some of your genetic and health information may be placed in central databases that 
may be public, along with information from many other people. Information that 
could directly identify you will not be included. 
 
WHAT ARE THE POSSIBLE RISKS? 
 
1) The most common risks related to drawing blood from your arm are brief pain and 
possibly a bruise.  
2) There is a risk that someone could get access to the personal information in your 
medical records or other information researchers have stored about you. 
3) There is a risk that someone could trace the information in a central database back to 
you. Even without your name or other identifiers, your genetic information is unique 
to you. The researchers believe the chance that someone will identify you is very 
small, but the risk may change in the future as people come up with new ways of 
tracing information. 
4) In some cases, genetic information could be used to make it harder for you to get or 
keep a job or insurance. There are laws against the misuse of genetic information, but 
they may not give full protection. There can also be a risk in knowing genetic 
information. New health information about inherited traits that might affect you or 
your blood relatives could be found during a study. The researchers believe that the 
chance that these things will happen is very small, but they cannot promise that you 
will avoid any risk. 
 
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE? 
 
Your privacy is very important to the researchers, and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your samples are sent to the researchers, no information identifying you (such 
as your name) will be sent. Samples will be identified by a unique code only.  
2) The list that links the unique code to your name will be kept separate from your 
sample and health information. Any Biobank and SWOG staff with access to the list 
must sign an agreement to keep your identity confidential. 
3) Researchers that receive your sample and information from SWOG will not know 
who you are. Researchers must also sign an agreement that they will not try to find 
out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not 
be used. 
 
WHAT ARE THE POSSIBLE BENEFITS? 
 
You will not benefit from taking part in this study.  The researchers, using the samples from you 
and others, might make discoveries that could help people in the future. 

 
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ARE THERE ANY COSTS OR PAYMENTS? 
 
There are no costs to you or your insurance. You will not be paid for taking part.  If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
WHAT IF I CHANGE MY MIND? 
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 researchers know. Then, any samples that remain in the bank will no longer be used. 
Samples or related information that have already been given to or used by researchers will not be 
returned. 
 
If you decide to withdraw your specimens from a SWOG Specimen Repository in the 
future, a written withdrawal of consent should be submitted through your study doctor to 
the SWOG Operations Office.  Please designate in the written withdrawal whether you 
would prefer to have the specimens destroyed or returned to the study doctor. 
 
WHAT IF I HAVE MORE QUESTIONS? 
 
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 to show whether or not you would like to take part in each option 
(include only applicable questions): 
 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
 
My samples and related information may be kept in a Biobank for use in future 
health research. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My Signature Agreeing to Take Part in the Main 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 copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 

 
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Specimen Consent Supplemental Sheets 
 
How are Specimens Used for Research? 
 
Where do specimens come from? 
 
A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials.  
People who are trained to handle specimens and protect donors' rights make sure that the highest 
standards of quality control are followed by SWOG.  Your doctor does not work for SWOG, but has 
agreed to help collect specimens from many patients.  Many doctors across the country are helping in the 
same way.   
 
Why do people do research with specimens? 
 
Research with specimens can help to find out more about what causes cancer, how to prevent it, how to 
treat it, and how to cure it.  Research using specimens can also answer other health questions.  Some of 
these include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's. 
 
What type of research will be done with my specimen? 
 
Many different kinds of studies use specimens.  Some researchers may develop new tests to find 
diseases.  Others may develop new ways to treat or even cure diseases.  In the future, some of the 
research may help to develop new products, such as tests and drugs.  Some research looks at diseases 
that are passed on in families (called genetic research).  Research done with your specimen may look for 
genetic causes and signs of disease. 
 
How do researchers get the specimen? 
 
Researchers from universities, hospitals, and other health organizations conduct research using 
specimens.  They contact SWOG and request samples for their studies.  SWOG reviews the way that 
these studies will be done, and decides if any of the samples can be used. SWOG gets the specimen and 
information about you from your hospital, and sends the specimen samples and some information about 
you to the researcher.  SWOG will not send your name, address, phone number, social security number 
or any other identifying information to the researcher. 
 
Will I find out the results of the research using my specimen? 
 
You will not receive the results of research done with your specimen.  This is because research can take 
a long time and must use specimen samples from many people before results are known.  Results from 
research using your specimen may not be ready for many years and will not affect your care right now, 
but they may be helpful to people like you in the future. 
 
Why do you need information from my health records? 
 
In order to do research with your specimen, researchers may need to know some things about you.  (For 
example:  Are you male or female?  What is your race or ethnic group? How old are you?  Have you ever 
smoked?)  This helps researchers answer questions about diseases.  The information that will be given to 
the researcher may include your age, sex, race, diagnosis, treatments and family history.  This 
information is collected by your hospital from your health record and sent to SWOG.  If more information 
is needed, SWOG will send it to the researcher. 
 
Will my name be attached to the records that are given to the researcher? 
 
No.  Your name, address, phone number and anything else that could identify you will be removed before 
they go to the researcher.  The researcher will not know who you are. 

 
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How could the records be used in ways that might be harmful to me? 
 
Sometimes, health records have been used against patients and their families.  For example, insurance 
companies may deny a patient insurance or employers may not hire someone with a certain illness (such 
as AIDS or cancer).  The results of genetic research may not apply only to you, but to your family 
members too.  For disease caused by gene changes, the information in one person's health record could 
be used against family members. 
 
How am I protected? 
 
SWOG is in charge of making sure that information about you is kept private.  SWOG will take careful 
steps to prevent misuse of records.  Your name, address, phone number and any other identifying 
information will be taken off anything associated with your specimen before it is given to the researcher.  
This would make it very difficult for any research results to be linked to you or your family.  Also, people 
outside the research process will not have access to results about any one person which will help to 
protect your privacy. 
 
What if I have more questions? 
 
If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert 
IRB's Phone Number).