A Phase III Blinded Study of Immediate Post TURBT Instillation of Gemcitabine Versus Saline in Patients With Newly Diagnosed or Occasionally Recurring Grade I/II Superficial Bladder Cancer
Phase: PHASE3
Conditions: Bladder Cancer
Sponsor: SWOG Cancer Research Network

v 
 
 
 
 
 
 
 
Distribution Date:  February 1, 2014 
CTEP Submission Date:  October 29, 2013 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS 
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer." Study Chairs:  
Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. Wood, Jr., and 
P.C. Mack. 
 
REVISION #7 
 
Study Chair: Edward M. Messing, M.D. 
Phone number: 585/275-3345 
E-mail: edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(√ ) 
Expedited review allowed 
 
(   ) 
No review required 
 
 
REVISION #7 
 
The above-referenced study has been updated as follows:   
 
 1.  
Face page: The version date of the protocol and model consent form have been 
updated (10/29/13). 
 
2. 
Page 25, Section 11.1, Primary Endpoint:  The 4th paragraph in this section 
has been revised in order to correct terms and assumptions for the statistical 
section specifications:   
 
 
Original 
“Two interim analyses of time-to-recurrence will be performed after 50% and 80% 
of the expected number of events have occurred (126 and 202 relapses, 
respectively, assuming the alternative treatment hypothesis) which will be 
approximately at the time accrual is completed and one year later. Consideration 
will be given to reporting early at either time if (1) TTR on the gemcitabine arm is 

 
S0337 
 
Revision #7 (contd.) 
 
Page 2 
 
 
 
superior at the one-sided 0.005 level or if (2) the hypothesis λ=1.53 (where λ is 
the sterile water/gemcitabine hazard ratio) is rejected in favor of λ<1.53 at the 
one-sided 0.005 level (testing using a proportional hazards score test, an 
extension of the logrank test).” 
 
New 
“Two interim analyses of time-to-recurrence will be performed after 50% and 80% 
of the expected number of events have occurred (126 113 and 202 181 relapses, 
respectively, assuming the alternative treatment hypothesis) which will be 
approximately at the time accrual is completed and one year later. Consideration 
will be given to reporting early at either time if (1) TTR on the gemcitabine arm is 
superior at the one-sided 0.005 level or if (2) the hypothesis λ=1.53 (where λ is 
the sterile water/gemcitabine hazard ratio) is rejected in favor of λ<1.53 at the 
one-sided 0.005 level (testing using a proportional hazards score test, an 
extension of the logrank test).” 
 
Please attach this memorandum to the front of your copy of the protocol. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Cathy M. Tangen, Dr.P.H. 
 
Hongli Li, M.S. 
 
Jean Barce 
Austin Hamm 
Brian Zeller 
Steven Nicol, M.D. – Lilly 
Barbra Podesta, R. Ph. – Lilly 
Erin Fink – Lilly 
Joseph J. Ashland - Lilly 
Kathy Brown – Pharmagistics 
Thomas King – Pharmagistics 
 

 
 
 
 
 
 
Distribution Date:  October 15, 2013 
CTEP Submission Date:  August 29, 2013 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS 
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer." Study Chairs:  
Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. Wood, Jr., and 
P.C. Mack. 
 
REVISION #6 
 
Study Chair: Edward M. Messing, M.D. 
Phone number: 585/275-3345 
E-mail: edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(√ ) 
Expedited review allowed 
 
(   ) 
No review required 
 
 
REVISION #6 
 
The protocol has been reformatted and repaginated to meet the current requirements for 
electronic protocol submission. This includes addition of second level headings in 
instances where they were previously absent, reformatting the title page to include all 
second level headings, reformatting the protocol calendar into Microsoft® Word, removal 
of forms and form numbers, and removal of the consent document as Section 18.0.  
Additionally, cross-references have been corrected as needed.  
 
1.   
Face page (Page 1):  The following changes have been made to this page: 
 
The version date has been updated (8/29/13).   
 
The heading “Study Coordinators” has been changed to “Study Chairs”.  The 
change from “Study Coordinator” to “Study Chair” was also made throughout 
the protocol in Section 7.1 (page 18), Section 8.5 (page 21), and Section 
11.3 (page 26).   
 
The heading “Biostatisticians” has been added above the contact information 
for the biostatisticians. 
 
2. 
Page 22, Section 9.0:  References to Sections 15.4 and 15.3 have been 
corrected to 15.1 and 15.2, respectively.   
 

 
S0337 
 
Revision #6 (contd.) 
 
Page 2 
 
 
 
3. 
Page 25, Section 11.1:  The following section has been revised in order to clarify 
terms and assumptions for the statistical section specifications:   
 
Original 
“If one assumes roughly equal numbers of patients with newly diagnosed and 
recurrent superficial bladder tumors, then we anticipate about 60% of patients will 
experience recurrences by 2 years. It is assumed that 14 eligible patients per 
month will be randomized. Patients will be stratified by disease status (first 
occurrence vs. recurrent disease), and number of tumors (one versus more than 
one).  Assuming exponential time-to-recurrence (TTR) and 40% TTR at two 
years in the sterile saline group, then two years of accrual (340 eligible patients) 
and two additional years of follow-up will be required for a one-sided 0.025 level 
test to have power 0.89 for detecting a hazard ratio of 1.53 (equivalent to an 
improvement to a 55% TTR rate at two years on the gemcitabine arm).  The 
primary test will be performed using the stratified logrank test.  All eligible, 
randomized patients will be used in the primary analysis regardless of whether 
they actually receive the treatment to which they were assigned (intent-to-treat 
analysis). 
 
Estimate of sample size: 340 eligible 
Estimate of accrual rate: 170 eligible/year 
 
Two interim analyses of time-to-recurrence will be performed after 50% and 80% 
of the expected number of events have occurred (126 and 202 relapses, 
respectively) which will be approximately at the time accrual is completed and 
one year later.  Consideration will be given to reporting early at either time if (1) 
TTR on the gemcitabine arm is superior at the one-sided 0.005 level or if (2) the 
hypothesis λ=1.53 (where λ is the sterile water/gemcitabine hazard ratio) is 
rejected in favor of λ<1.53 at the one-sided 0.005 level (testing using a 
proportional hazards score test, an extension of the logrank test). 
 
Assuming the study does not terminate early, the final analysis will occur when 
approximately 252 recurrences have been reported (estimated to be about two 
years after completion of accrual).  The final analysis will be based on the 
stratified logrank test with stratification factors as specified in Section 6.0 with a 
one-sided 0.020 level to adjust for the two interim analyses, for an overall level of 
0.025 (one-sided). In addition, the trial will be monitored for safety every six 
months.” 
 
New 
“If one assumes roughly equal numbers of patients with newly diagnosed and 
recurrent superficial bladder tumors, then we anticipate about 60% of patients will 
experience recurrences by 2 years. It is assumed that 14 eligible patients per 
month will be randomized. Patients will be stratified by disease status (first 
occurrence vs. recurrent disease), and number of tumors (one versus more than 
one).  Assuming exponential time-to-recurrence (TTR) and 40% 60% TTR (40% 
recurrence-free) at two years in the sterile saline group, then two years of 
accrual (340 eligible patients) and two additional years of follow-up will be 
required for a one-sided 0.025 level test to have power 0.89 for detecting a 
hazard ratio of 1.53 (equivalent to an improvement to a 55% 45% TTR (55% 
recurrence-free) rate at two years on the gemcitabine arm).  The primary test 
will be performed using the stratified logrank test.  All eligible, randomized 
patients will be used in the primary analysis regardless of whether they actually 
receive the treatment to which they were assigned (intent-to-treat analysis). 
 
Estimate of sample size: 340 eligible 
Estimate of accrual rate: 170 eligible/year 

 
S0337 
 
Revision #6 (contd.) 
 
Page 3 
 
 
 
Two interim analyses of time-to-recurrence will be performed after 50% and 80% 
of the expected number of events have occurred (126 and 202 relapses, 
respectively, assuming the alternative treatment hypothesis) which will be 
approximately at the time accrual is completed and one year later.  Consideration 
will be given to reporting early at either time if (1) TTR on the gemcitabine arm is 
superior at the one-sided 0.005 level or if (2) the hypothesis λ=1.53 (where λ is 
the sterile water/gemcitabine hazard ratio) is rejected in favor of λ<1.53 at the 
one-sided 0.005 level (testing using a proportional hazards score test, an 
extension of the logrank test). 
 
Assuming the study does not terminate early and the alternative treatment 
hypothesis, the final analysis will occur when approximately 252 226 
recurrences have been reported (estimated to be about two years after 
completion of accrual).  The final analysis will be based on the stratified logrank 
test with stratification factors as specified in Section 6.0 with a one-sided 0.020 
level to adjust for the two interim analyses, for an overall level of 0.025 (one-
sided). In addition, the trial will be monitored for safety every six months and 
assuming the alternative hypothesis holds.” 
 
4. 
Page 29, Section 14.2, Master Forms:  The following section has been revised 
for editorial purposes as follows: 
 
 
Original 
“Master forms are included in Section 18.0 and (with the exception of the sample 
consent form and the Registration Form) must be submitted to the Data 
Operations Center in Seattle. Data from approved SWOG institutions must be 
submitted on-line via the Web; see Section 14.3a for details. Exceptions to online 
data submission are patient completed (e.g. Quality of Life) forms and source 
documents (e.g. pathology/operative/lab reports).” 
 
New 
“Master forms are included in Section 18.0 can be found on the protocol 
abstract page on the SWOG website (www.swog.org) and (with the exception 
of the sample consent form and the Registration FormWorksheet) must be 
submitted to the Data Operations Center in Seattle on-line via the Web; Data 
from approved SWOG institutions must be submitted on-line via the Web; see 
Section 14.3a for details. Exceptions to online data submission are patient 
completed (e.g. Quality of Life) forms and source documents (e.g. 
pathology/operative/lab reports).” 
 
 
An entire replacement protocol is attached. Please discard any previous 
versions of the protocol, and attach this memorandum to the front of your 
copy of S0337. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
Cathy M. Tangen, Dr.P.H. 
 
Hongli Li, M.S. 
 
Jean Barce 
Austin Hamm 
Brian Zeller 
Steven Nicol, M.D. – Lilly 
Barbra Podesta, R. Ph. – Lilly 
Erin Fink – Lilly 
Joseph J. Ashland - Lilly 
Kathy Brown – Pharmagistics 
Thomas King – Pharmagistics 

 
 
 
 
 
 
 
 
July 15, 2012 
 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS 
 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. 
Wood, Jr., and P. C. Mack. 
 
STATUS NOTICE 
 
Study Coordinator:  Edward M. Messing, M.D. 
Phone number:  585/275-3345 
E-mail:  edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) 
Expedited review allowed 
 
(   ) 
No review required 
 
 
PERMANENT CLOSURE 
 
The above-referenced protocol has met its accrual goal and will be permanently closed to 
accrual effective 11:59 p.m. on August 15, 2012. 
 
Please attach this memorandum to the front of your copy of the protocol.     
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Barbra Podesta, R. Ph. – Lilly 
Hongli Li, M.S. 
Erin Fink – Lilly 
Jean Barce 
Joseph J. Ashland - Lilly 
Austin Hamm 
Kathy Brown – Pharmagistics 
Brian Zeller 
Thomas King – Pharmagistics 
Steven Nicol, M.D. – Lilly 
 
 

 
 
 
 
 
 
 
 
Distribution Date: 
July 15, 1012 
CTEP Submission Date: 
June 19, 2012 
 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS 
 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. 
Wood, Jr., and P. C. Mack. 
 
REVISION #5 
 
Study Coordinator:  Edward M. Messing, M.D. 
Phone number:  585/275-3345 
E-mail:  edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) 
Expedited review allowed 
 
(   ) 
No review required 
 
 
REVISION #5 
 
The above-referenced protocol has been revised as follows: 
 
Face Page:  The participants list was revised to delete “UCOP” as this program has been 
discontinued.  The contact information for Dr. Koppie has been updated.  Bryan Goldman 
is no longer with the Group.  His name and contact information has been replaced with 
that for Hongli Li, M.S.  The version date has been updated. 
 
Page 1a:  The contact information for Dr. Wood has been updated. 
 
Section 7.0, page 15:  The phone number for Dr. Wood has been revised. 
 
Section 7.3, page 16:  The form number for the S0337 Cystoscopy and Urine Markers 
Form has been updated from Form #7491 to Form #42978. 

 
S0337 
 
Revision #5 (contd.) 
 
Page 2 
 
 
 
 
Section 8.6, page 17:  This section has been revised to reflect the Group’s current 
standard language regarding reporting toxicities. 
 
Section 13.3a, page 23:  The phone number for the SWOG Operations Office has been 
updated. 
 
Section 14.3a, page 24:  The phone number for the SWOG Operations Office has been 
updated. 
 
Sections 14.4 and 14.6, page 25:  The form number for the S0337 Cystoscopy and 
Urine Markers Form has been updated from Form #7491 to Form #42978. 
 
Section 15.0, pages 25-27:  This section has been updated so that the format is 
consistent the Group’s current specimen submission instructions.  The types of 
specimens collected, the frequency at which they are collected, and how they are 
collected has not changed. 
 
Section 16.1, pages 28-30:  This section has been updated to reflect the Group’s current 
SAE reporting guidelines.   
 
Section 18.2e, page 33:  The S0337 Cystoscopy and Urine Markers Form has been 
revised and the form number has been changed from Form # 7491 to Form #42798.  The 
form itself was revised to add a check box for Month 42 which was inadvertently omitted. 
 
Section 19.1, pages 59-60:  This section has been revised to reflect the Group’s current 
standard language regarding determination of expedited adverse event reporting 
requirements. 
 
Section 19.3, page 63:  The form number for the S0337 Cystoscopy and Urine Markers 
Form has been updated from Form #7491 to Form #42978. 
 
Please attach this memorandum to the front of your copy of the protocol.     
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
 
Hongli Li, M.S. 
 
Jean Barce 
 
Austin Hamm 
 
Brian Zeller 
 
Steven Nicol, M.D. – Lilly 
 
Barbra Podesta, R. Ph. – Lilly 
Erin Fink – Lilly 
Joseph J. Ashland - Lilly 
Kathy Brown – Pharmagistics 
Thomas King – Pharmagistics 
 

 
 
 
 
 
 
February 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Gemcitabine hydrochloride (Gemzar®) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following revised safety report has been posted regarding an adverse event that 
occurred in association with the blinded drug gemcitabine hydrochloride/placebo. This 
report downgraded the event previously reported such that the event is no longer 
reportable. Please access this safety report via the study’s abstract page or the safety 
report link on the SWOG website (https://swog.org/safetyreports/safetyreports.asp). 
 
This safety report pertains to the following study:
 
 
 
S0337 Genitourinary 
Report: 
 
Dec. 27, 2011 AE #US201111007133 FU
 
A protocol amendment is not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Steven Nicol, M.D.–Lilly 
 
Cathy M. Tangen, Dr.P.H. 
Barbra Podesta, R.Ph.–Lilly 
 
Benjamin W. Ely, M.S. 
Erin Fink–Lilly 
 
Jean Barce 
Joseph J. Ashland–Lilly 
 
Austin Hamm 
Kathy Brown–Pharmagistics 
 
Brian Zeller 
Thomas King–Pharmagistics 

 
 
 
 
 
 
 
January 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Gemcitabine hydrochloride (Gemzar®) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug gemcitabine hydrochloride. Please access this 
safety report via the study’s abstract page or the safety report link on the SWOG website 
(https://swog.org/safetyreports/safetyreports.asp). 
 
This safety report pertains to the following study:
 
 
 
S0337 Genitourinary 
Report: 
 
Dec. 1, 2011 AE #US201111007133 
 
A protocol amendment is not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Steven Nicol, M.D.–Lilly 
 
Cathy M. Tangen, Dr.P.H. 
Barbra Podesta, R.Ph.–Lilly 
 
Benjamin W. Ely, M.S. 
Erin Fink–Lilly 
 
Jean Barce 
Joseph J. Ashland–Lilly 
 
Austin Hamm 
Kathy Brown–Pharmagistics 
 
Brian Zeller 
Thomas King–Pharmagistics 

 
 
 
 
 
 
December 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. 
Wood, Jr., and P. C. Mack. 
 
MEMORANDUM 
 
Study Coordinator:  Edward M. Messing, M.D. 
Phone number:  585/275-3345 
E-mail:  edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(   ) 
Expedited review allowed 
 
( √ ) 
No review required 
 
 
MEMORANDUM 
 
The purpose of this memorandum is to inform sites of the Holiday closure of 
Pharmagistics/Knipper.  They will be closed Friday, December 23, 2011 through 
Monday, December 26, 2011.  Regular business hours and shipping will resume on 
Tuesday, December 27, 2011. 
 
As a reminder, if a patient consents to the optional specimen submission, you must 
contact Dr. Jay Reeder's lab as noted in Section 15.3 of the protocol after the patient is 
registered and the Month 3 visit is scheduled to order a Paxgene blood tube well in 
advance of the Month 3 blood draw. 
 
Please attach this memorandum to the front of your copy of the protocol.     
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Barbra Podesta, R. Ph. – Lilly 
Benjamin W. Ely, M.S. 
Erin Fink – Lilly 
Jean Barce 
Joseph J. Ashland - Lilly 
Austin Hamm 
Kathy Brown – Pharmagistics 
Brian Zeller 
Thomas King – Pharmagistics 
Steven Nicol, M.D. – Lilly 
 

 
 
 
 
 
 
Distribution Date: 
December 1, 2010 
CTEP Submission Date:   
November 19, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP, AFFILIATE, 
AND 
UCOP 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. 
Wood, Jr., and P. C. Mack. 
 
REVISION #4 
 
Study Coordinator:  Edward M. Messing, M.D. 
Phone number:  585/275-3345 
E-mail:  edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
 (   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) 
Expedited review allowed 
 
 (    ) 
No review required 
 
 
REVISION #4 
 
The above-referenced protocol has been revised as follows: 
 
1. 
Title Page:  The version date has been updated. 
 
2. 
Pages 16-16a, Section 8.1:  The criteria for reporting Adverse Events have been 
updated.  Effective January 1, 2011 the CTCAE Version 4.0 will be utilized for 
SAE reporting.  The CTCAE Version 3.0 will continue to be utilized for routine 
toxicity reporting.  Page 16a was added to prevent extensive repagination. 
 
Please append this notice to the front of your protocol and insert the replacement pages 
referenced above. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Steven Nicol, M.D. – Lilly 
Bryan Goldman, M.S. 
Barbra Podesta, R. Ph. – Lilly 
Benjamin W. Ely, M.S. 
Erin Fink – Lilly 
Jean Barce 
Joseph J. Ashland - Lilly 
Janice Leaman 
Kathy Brown – Pharmagistics 
Brian Zeller 
Thomas King – Pharmagistics 

 
 
 
 
 
Distribution Date: 
November 15, 2009 
CTEP Submission Date: 
October 21, 2009  
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP, AFFILIATE, 
AND 
UCOP 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. 
Wood, Jr., and P. C. Mack.  
 
REVISION #3 
 
Study Coordinator: 
Edward M. Messing, M.D. 
Phone: 
585/275-3345 
E-mail: 
edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) No review required 
 
 
REVISION #3 
 
The above-referenced protocol has been revised as follows: 
 
Face Page:  The version date of the protocol has been updated. 
 
Section 3.1c, page 12:  Two sentences have been added to the "Supplier" paragraph of 
Section 3.1c to provide logistical information for Saturday drug delivery for patients 
registered on Thursday after 2 p.m. Eastern time, but prior to 2. p.m. Eastern time on 
Friday. 
 
Section 5.1, page 13:  This section has been revised as follows:  The bullet point "have 
had no prior bladder cancer for ≥ 9 months before the index tumor resection" has been 
deleted.  The now second bullet point has been revised to indicate that patient must have 
had no more than 2 recurrences in the 18 months (versus 3 years) preceding index tumor’s 
TURBT.  Additionally this bullet point has been revised to indicate allowable stages of 
these recurrences. 
 
Section 5.2, page 13:  This section has been revised to indicate that there must be plans 
for the patient to receive a TURBT within 28 working days rather than ten working days 
after randomization. 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 

 
S0337 
 
Revision #3 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
Section 5.3, page 13:  This section has been revised to indicate that patients must not 
have received previous intravesical therapy within 145 days rather than 180 days. 
 
Section 5.4, page 13:  This section has been revised to clarify to define negative urine 
analysis for infection. 
 
Section 5.8, page 14:  This section has been revised to allow patients free of disease for 
three years rather than five years. 
 
Section 7.1g, page 15:  This section has been revised to indicate that patient should have 
negative upper tract imaging studies obtained within 365 days prior to registration rather 
than within 180 days. 
 
Section 7.2, page 15:  This section has been revised to be consistent with the revision 
made in Section 5.2 as noted above. 
 
Section 13.1, page 22:  This section has been revised to be consistent with the revision 
made in Section 5.2 as noted above. 
 
Prestudy Form:  The Prestudy Form has been revised to be consistent with the changes 
made in Section 5.0 of the protocol.  Section 5.0, page 13, Section 14.4, page 25, and 
Section 18.2b, page 33 have been revised to cross reference the new form number 
(#19450) instead of Form #23033. 
  
 
Please append this notice to the front of your protocol and insert the replacement pages 
referenced above. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Bryan Goldman, M.S. 
Benjamin W. Ely, M.S. 
Jean Barce 
Janice Leaman 
Brian Zeller 
Steven Nicol, M.D. – Lilly 
Barbra Podesta, R. Ph. – Lilly 
Erin Fink – Lilly 
Joseph J. Ashland - Lilly 
Kathy Brown – Pharmagistics 
Thomas King – Pharmagistics 

 
 
 
 
 
Distribution Date: 
June 1, 2009 
CTEP Submission Date: 
May 15, 2009  
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP, AFFILIATE, 
AND 
UCOP 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. 
Wood, Jr., and P. C. Mack.  
 
REVISION #2 
 
Study Coordinator: 
Edward M. Messing, M.D. 
Phone: 
585/275-3345 
E-mail: 
edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(   ) No review required 
 
 
REVISION #2 
 
The above-referenced protocol has been revised as follows: 
 
Face Page:  The version date of the protocol has been revised. 
 
Section 3.1c, page 12:  The last sentence of the "Supplier" section has been revised to 
more accurately reflect that each investigator must be linked to an active pharmacy in the 
SWOG database. 
 
Section 5.4, page 13:  For clarification, this section has been revised to move the end 
parenthesis in the second line; capitalize, underline and bold the text "OR"; and replace the 
word "and" with "with".  Additionally, the third line of this section has been revised to 
indicate that patients must have WBC/HPF of ≤ 10 instead ≤ 2.  
 
Please append this notice to the front of your protocol and insert the replacement pages 
referenced above. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Steven Nicol, M.D. – Lilly 
Bryan Goldman, M.S. 
Barbra Podesta, R. Ph. – Lilly 
Benjamin W. Ely, M.S. 
Erin Fink – Lilly 
Jean Barce 
Kathy Brown – Pharmagistics 
Janice Leaman 
Thomas King – Pharmagistics 
Brian Zeller 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 

 
 
 
 
 
Distribution Date: 
February 1, 2009 
CTEP Submission Date: 
December 30, 2008  
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP, AFFILIATE, 
AND 
UCOP 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, T.M. Koppie, D.P. 
Wood, Jr., and P. C. Mack.  
 
REVISION #1 
 
Study Coordinator: 
Edward M. Messing, M.D. 
Phone: 
585/275-3345 
E-mail: 
edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
REVISION #1 
 
The above-referenced protocol has been revised as follows: 
 
Face Page:  Dr. Theresa M. Koppie has been added as a Secondary Study Coordinator 
and her contact information included.  The version date has been revised. 
 
Section 3.1c, page 12:  Two sentences have been added to the “Supplier” section of 
Section 3.1c to clarify drug shipping and delivery timeframes.  The last sentence of the 
"Supplier" section has been revised to clarify that the pharmacist will need the patient 
number in order to identify the correct package from the drug distributor. 
 
Sections 5.3 and 5.4, pages 13-14:  Sections 5.3 and 5.4 have been moved to the Good 
Medical Practice Section (Section 7.1, page 15) and the remainder of Section 5.0 
renumbered accordingly.  A sentence was added to Section 5.4 (now Section 7.1g) to 
indicate that the imaging studies may be performed after registration, but prior to TURBT 
on the day of the treatment. 
 
Section 7.1f&g, page 15:  These sections have been added as indicated above and the 
text "must" has been revised to "should." 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 

 
S0337 
 
Revision #1 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
 
Section 7.3, page 16:  The second sentence of this section has been revised to indicate 
that the BTA Stat and NMP-22 Bladder Check are commercially available tests.  The last 
sentence of this section has been revised to replace the text “specimen kits” with “tests.” 
 
Section 9.0, page 18:  The "£"footnote has been added to the Study Calendar. 
 
Section 11.2, page 20:  The text “sterile water” has been replaced with “saline” in the 
second paragraph of this section. 
 
Section 15.3, page 26:  This section has been revised to update the phone number for Dr. 
Reeder (Lab #135) and clarify the blood submission procedure. 
 
Page 1a was added to prevent extensive repagination of the protocol. 
 
Please append this notice to the front of your protocol and insert the replacement pages 
referenced above. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Bryan Goldman, M.S. 
Benjamin W. Ely, M.S. 
Jean Barce 
Janice Leaman 
Brian Zeller 
Steven Nicol, M.D. – Lilly 
Barbra Podesta, R. Ph. – Lilly 
Erin Fink – Lilly 
Kathy Brown – Pharmagistics 
Thomas King – Pharmagistics 
 
 

 
 
 
 
 
September 1, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP, AFFILIATE, 
AND 
UCOP 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, D.P. Wood, Jr., and P. 
C. Mack.  
 
MEMORANDUM 
 
Study Coordinator: 
Edward M. Messing, M.D. 
Phone: 
585/275-3345 
E-mail: 
edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
(   ) Expedited review allowed 
 
( √ ) No review required 
 
 
MEMORANDUM 
 
Please note that the intellectual property terms applicable to participation in this trial, as 
partially funded by an industry collaborator, are different from the terms set forth in the 
Purchase Service Agreement (PSA) signed by registering members.  Specifically, 
participation in this trial requires agreement and compliance with allowing the industry 
collaborator a non-exclusive license to any intellectual property resulting from this trial, 
including use for commercial purposes.  This is in contrast to the standard intellectual 
property terms in the PSA which restricts the industry collaborator to a non-exclusive 
license for research purposes only.  This exception to the standard intellectual property 
terms has been approved by the NCI.  You are required to inform your site’s appropriate 
grants and contracts office about this modification to the PSA.  Please direct any questions 
related to this modification to the legal department at Group Headquarters Office at 734-
998-7173. 
 
Please attach this memorandum to the front of your copy of the protocol.     
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Steven Nicol, M.D. – Lilly 
Bryan Goldman, M.S. 
Barbra Podesta, R. Ph. – Lilly 
Jean Barce 
Shane E. Feys – Lilly 
Janice Leaman 
Kathy Brown – Pharmagistics 
Brian Zeller 
Thomas King – Pharmagistics 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 

 
 
 
 
 
July 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP, AFFILIATE, 
AND 
UCOP 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS 
 
FROM: 
Jennifer I. Scott, Protocol Coordinator 
 
RE: 
S0337, "A Phase III Blinded Study of Immediate Post-TURBT Instillation of 
Gemcitabine Versus Saline in Patients with Newly Diagnosed or 
Occasionally Recurring Grade I/II Superficial Bladder Cancer."  Study 
Coordinators:  Drs. E.M. Messing, D.M. Sahasrabudhe, D.P. Wood, Jr., and P. 
C. Mack.  
 
STATUS NOTICE 
 
Study Coordinator: 
Edward M. Messing, M.D. 
Phone: 
585/275-3345 
E-mail: 
edward_messing@urmc.rochester.edu 
 
IRB Review Requirements 
 
 ( √ ) Full board review required.  Reason: 
 
( √ ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
 (    ) Expedited review allowed 
 
 (    ) No review required 
 
 
ACTIVATION 
 
The study referenced above is now open for participation.  An entire copy of the protocol is 
enclosed for your use. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
Cathy M. Tangen, Dr.P.H. 
Bryan Goldman, M.S. 
Jean Barce 
Janice Leaman 
Monica Toth, M.S. 
Brian Zeller 
Steven Nicol, M.D. – Lilly 
Barbra Podesta, R. Ph. – Lilly 
Shane E. Feys – Lilly 
Kathy Brown – Pharmagistics 
Thomas King – Pharmagistics 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 

Revised 12/30/08 
S0337 
Revised 6/19/12 
Page 1 
 
Version Date 10/29/13 
 
Revised 8/29/13 
 
PRIVILEGED COMMUNICATION 
Activated July 15, 2007 
FOR INVESTIGATIONAL USE ONLY 
 
 
 
SWOG 
 
A PHASE III BLINDED STUDY OF IMMEDIATE POST-TURBT INSTILLATION OF GEMCITABINE 
VERSUS SALINE IN PATIENTS WITH NEWLY DIAGNOSED OR OCCASIONALLY 
 
RECURRING GRADE I/II SUPERFICIAL BLADDER CANCER 
 
 
PARTICIPANTS: ALL SOUTHWEST ONCOLOGY GROUP MEMBER, AFFILIATE AND CCOP 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS 
 
STUDY CHAIRS: 
AGENTS: 
 
Edward M. Messing, M.D. (Urology) 
Gemcitabine hydrochloride (Gemzar®)  
University of Rochester 
 
(NSC-613327) (IND-73,058) 
Strong Memorial Hospital 
Saline Placebo 
601 Elmwood Avenue, Box 656 
 
Rochester, NY 14642-0001 
 
Phone:  585/275-3345 
 
Fax:  585/442-8350 
 
E-Mail:  edward_messing@urmc.rochester.edu 
 
 
 
Deepak M. Sahasrabudhe, M.D. (Medical Oncology) 
Philip C. Mack, Ph.D. (Molecular Biology) 
University of Rochester 
UC Davis Cancer Center 
Strong Memorial Hospital 
Division of Hematology/Oncology 
601 Elmwood Avenue 
4501 X Street 
Box 704 
Sacramento, CA 95817 
Rochester, NY  14642-0001 
Phone:  916/734-3734 
Phone:  585/275-4797 
Fax:  916/734-2361 
Fax:  585/273-1042 
E-Mail:  pcmack@ucdavis.edu 
E-Mail:  deepak_sahasrabudhe@urmc.rochester.edu 
 
 
BIOSTATISTICIANS: 
 
Theresa M. Koppie, M.D. (Urology) 
Cathy M. Tangen, Dr.P.H. (Biostatistics) 
OHSU 
Hongli Li, M.S. 
3303 SW Bond Avenue 
Southwest Oncology Group Statistical Center 
Portland, OR  97239 
Fred Hutchinson Cancer Research Center 
Phone:  503/346-1500  
1100 Fairview Avenue North, M3-C102 
Fax:  503/346-1501 
P.O. Box 19024 
E-mail:  koppie@ohsu.edu 
Seattle, WA 98109-1024 
 
Phone:  206/667-4623 
 
Fax:  206/667-4408 
David P. Wood, Jr., M.D. (Urology) 
E-Mail:  ctangen@fhcrc.org 
Beaumont Physician Partners 
E-Mail:  hongli@fhcrc.org 
3711 W. 13 Mile Road 
 
Royal Oak, MI  48073 
 
Phone:  248/551-0678  
 
E-Mail:  dpwood@beaumont.edu 
 
 
 
 

 
S0337 
 
Page 2 
 
Version Date 10/29/13 
 
TABLE OF CONTENTS 
 
Page 
 
SCHEMA ..................................................................................................................................... 4 
1.0 
OBJECTIVES................................................................................................................. 5 
1.1 
Primary Objective ........................................................................................................... 5 
1.2 
Secondary Objectives .................................................................................................... 5 
1.3 
Translational Medicine Objectives ................................................................................. 5 
2.0 
BACKGROUND ............................................................................................................. 5 
3.0 
DRUG INFORMATION ................................................................................................. 11 
3.1 
Gemcitabine hydrochloride (Gemzar®) (NSC-613327) (IND-73,058) ........................... 11 
4.0 
STAGING CRITERIA (AJCC Sixth Edition, 2002) ...................................................... 15 
5.0 
ELIGIBILITY CRITERIA ............................................................................................... 16 
5.1 
Disease Related Criteria ............................................................................................... 16 
5.2 
Prior Therapy Criteria .................................................................................................... 16 
5.3 
Clinical/Laboratory Criteria ............................................................................................ 16 
5.4 
Specimen Submission Criteria ...................................................................................... 17 
5.5 
Regulatory Criteria ........................................................................................................ 17 
6.0 
STRATIFICATION FACTORS ...................................................................................... 18 
7.0 
TREATMENT PLAN ..................................................................................................... 18 
7.1 
Good Medical Practice .................................................................................................. 18 
7.2 
Treatment ...................................................................................................................... 18 
7.3 
NMP-22 Bladder Chek and BTA Stat Testing ............................................................... 19 
7.4 
Criteria for Removal from Protocol Treatment .............................................................. 19 
7.5 
Emergency Unblinding .................................................................................................. 19 
7.6 
Discontinuation of Treatment ........................................................................................ 20 
7.7 
Follow Up Period ........................................................................................................... 20 
8.0 
DOSAGE MODIFICATIONS ......................................................................................... 20 
8.1 
NCI Common Terminology Criteria for Adverse Events. .............................................. 20 
8.2 
General Dose Modification Considerations ................................................................... 20 
8.3 
Gemcitabine Dose Modifications. .................................................................................. 20 
8.4 
Dose Modification Contacts .......................................................................................... 21 
8.5 
Adverse Event reporting ................................................................................................ 21 
9.0 
STUDY CALENDAR ..................................................................................................... 22 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................................ 24 
10.1 
Recurrence .................................................................................................................... 24 
10.2 
Time to Recurrence ....................................................................................................... 24 
10.3 
Progression ................................................................................................................... 24 
10.4 
Time to Progression ...................................................................................................... 24 
10.5 
Performance Status ....................................................................................................... 24 
10.6 
Worsening-free Survival ................................................................................................ 24 
10.7 
Time to Death ................................................................................................................ 24 
11.0 
STATISTICAL CONSIDERATIONS ............................................................................. 25 
11.1 
Primary Endpoint ........................................................................................................... 25 
11.2 
Secondary Endpoints .................................................................................................... 25 
11.3 
Sensitivity and Specificity of Assays for Predicting Recurrence .................................... 26 
11.4    Data and Safety Monitoring Committee Oversight ........................................................ 27 
12.0 
DISCIPLINE REVIEW ................................................................................................... 28 
13.0 
REGISTRATION GUIDELINES .................................................................................... 28 
13.1 
Registration Timing ....................................................................................................... 28 
13.2 
Phone or Web Registration ........................................................................................... 28 
13.3 
Registration procedures ................................................................................................ 28 
13.4 
For either method of registration, exceptions to Southwest Oncology Group  ................ 
 
 
registration policies will not be permitted. ...................................................................... 29 
 

 
S0337 
 
Page 3 
 
Version Date 10/29/13 
 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................ 29 
14.1 
Data Submission Requirements .................................................................................... 29 
14.2 
Master Forms ................................................................................................................ 29 
14.3 
Data Submission Procedures ........................................................................................ 30 
14.4 
Data Submission Overview and Timepoints ................................................................. 30 
15.0 
SPECIAL INSTRUCTIONS ........................................................................................... 31 
15.1 
Tissue Specimens for Banking for Future Studies of As Yet To Be Determined  ........... 
 
 
Molecular Markers ......................................................................................................... 31 
15.2 
Whole Blood Specimens for Banking for Genotyping ................................................... 31 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 33 
16.1 
Adverse Event Reporting Requirements ....................................................................... 33 
17.0 
BIBLIOGRAPHY ........................................................................................................... 38 
18.0 
APPENDIX .................................................................................................................... 40 
18.1 
Determination of Expedited Adverse Event Reporting Requirements .......................... 41 
18.2 
Emergency Unblinding Guidelines ................................................................................ 43 
18.3 
Correlative Studies for S0337 ....................................................................................... 45 
 
 

 
S0337 
 
Page 4 
 
Version Date 10/29/13 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
Bladder Cancer 
Grade 1 or 2, Ta or T1 TCC 
 
 
 
 
 
 
RANDOMIZE 
 
 
 
 
 
 
TURBT+ 
TURBT+ 
Gemcitabine (Blinded) 
Saline (Blinded) 
 
 
 
 
 
Follow for 4 Years 
 
 
 

 
S0337 
 
Page 5 
 
Version Date 10/29/13 
 
 
1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
The primary objective of this study is to determine the efficacy of a single post-
transurethral resection of the bladder (TURBT) intravesical instillation of gemcitabine 
versus saline in preventing recurrence of completely resected Grade 1 or 2, Ta or T1 
transitional cell cancer (TCC) of the bladder at two years. 
 
1.2 
Secondary Objectives  
 
a. 
To test whether a single instillation of intravesical gemcitabine can improve the 
time to progression to muscle invasive disease compared to saline in this patient 
population. 
 
b. 
To compare the qualitative and quantitative toxicities between the arms. 
 
c. 
To determine if effective post TURBT instillation therapy results in reduced long 
term morbidity as determined by patients randomized to gemcitabine requiring 
fewer TURBTs, courses of traditional intravesical therapies, and surveillance 
cystoscopies over four years compared with those randomized to intravesical 
saline. 
 
1.3 
Translational Medicine Objectives 
 
a. 
The correlative studies will evaluate whether performing a combination of 
molecular/cytologic diagnostic marker tests including NMP-22 Bladder Chek and 
BTA Stat every three months can predict recurrence as accurately as cystoscopy 
alone. 
 
b. 
To acquire blood and tissue specimens from patients on this clinical trial for 
banking for genotyping. 
 
 
2.0 
BACKGROUND 
 
Overview 
 
While well- and moderately-differentiated recurring superficial bladder cancer rarely progresses to 
a life threatening condition, repeated resections represent considerable morbidity for patients and 
expense for both patients and the healthcare system as a whole.  In several European studies, 
immediate post-TURBT instillations of chemotherapeutic agents including epirubicin, mitomycin-
C, doxorubicin, and thiotepa have been shown to decrease the likelihood of recurrence and to be 
well-tolerated.  (1-5) Despite these data, this type of therapy has not been embraced by American 
urologists as part of standard care for the management of low-grade superficial bladder cancer.  
 
Superficial Bladder Cancer 
 
Natural History:  Bladder cancer is the fifth most common solid malignancy diagnosed annually in 
the United States.  (6)  Between 75 - 80% of these cancers will be superficial (Stage TIS, Ta, T1), 
greater than 90% transitional cell carcinomas (urothelial cancer), and the majority well (Grade 1) 
or moderately (Grade 2) differentiated (roughly equivalent to tumors of low malignant potential and 
low-grade carcinoma by 1998 AJCC criteria, respectively).  (7)  If one eliminates patients with 
Grade III (high-grade) cancer or carcinoma-in-situ (CIS), the risk of recurrence after endoscopic 
resection alone, is quite high, but that of progression to muscle invasion, relatively 
 

 
S0337 
 
Page 6 
 
Version Date 10/29/13 
 
low.  (2-4)  Based upon a recently completed NCI/ILEX Corporation chemoprevention study (CN-
26534), roughly 60% of patients eligible for S0337 (assuming most patients have prior histories of 
bladder cancer), will be expected to experience a tumor recurrence within two years, as detected 
upon every three month cystoscopy.  Fewer than 20% of patients eligible for this study would be 
expected to experience grade progression upon first failure, and far less than this stage 
progression to T2+.  (2-4,8) 
 
The population eligible for this trial will be patients who have low (Stage Ta, low malignant 
potential [LMP]) to moderate (Stage T1, low grade) risk urothelial cancer of the bladder and 
whose primary urologist believes are not candidates for more prolonged courses of intravesical or 
more aggressive therapies based upon preoperative cystoscopic inspection, bladder cancer 
history, and other factors (e.g. upper tract evaluation, cytology results, tumor size, multifocality, 
etc.).  Although cystoscopic inspection for experienced urologists is usually a reliable predictor of 
tumor grade and stage, it is estimated that roughly 10% of cases will be eliminated after 
randomization and drug/placebo instillation, because high grade cancer, TIS or muscle invading 
cancer (Stage T2+) is documented on final histology, mandating more aggressive therapies.  (9)  
Additionally, another 5-10% of patients would be expected to have sufficiently deep, large or 
bloody resections that urologists would be hesitant to perform immediate post TURBT instillations.  
 
Mechanisms of Superficial Bladder Cancer Recurrence:  Particularly for LMP and low grade 
superficial bladder cancers, data would indicate that recurrences of seemingly completely 
resected tumors occur because of new tumor development at other regions of the urothelium 
(field effect), implantation of tumor cells derived from the original tumor in other sites of urothelium 
(presumably occurring spontaneously as well as because of perturbations induced by 
instrumentations such as cystoscopy and transurethral resection [TUR]), and because of failure to 
resect the original malignancy.  (5,10)  Evidence to support implantation includes differences in 
locations of primary tumors compared to recurrences with the former primarily located on the 
lateral bladder walls (70%) and trigone (20%); while recurrences frequently arise on the dome and 
anterior bladder wall.  (11)  Animal models also indicate that both spontaneous and mechanically 
facilitated implantation occurs.  Sites of urothelial injury are preferential sites of recurrence.  (12-
13)  A single, immediately post TURBT intravesical instillation of chemotherapy is primarily 
directed at reducing the rate of implantation, although it may have a beneficial effect on 
eliminating field effect tumors or persistent (incompletely resected) ones, as well. 
 
Intravesical Therapy:  To reduce the frequency of recurrences in these individuals at low risk for 
bladder cancer progression and at high risk for recurrence, intravesical therapy with a variety of 
chemo- and immunotherapeutic agents have been used.  Agents have included BCG, mitomycin-
C, doxorubicin, and thiotepa in the United States, as well as epirubicin and epodyl in Europe.  
Courses of instillation therapy starting days and weeks after the TURBT can reduce recurrences 
by 17 to 44% compared with controls.  (14-16)  These treatments, however, are not without 
considerable inconvenience, expense, and morbidities for patients with side effects including 
thrombocytopenia and leukopenia with thiotepa in 9% of patients, genital rash due to mitomycin in 
6% of patients, and bladder contracture in as many as 16% of those treated with doxorubicin and 
a smaller percentage of those treated with mitomycin.  Side effects from BCG therapy occur in 20 
- 45% of patients and can include high fever, granulomatous prostatitis, pneumonitis, and 
hepatitis. 
 
To reduce these sources of morbidity, inconvenience and expense immediately following TURBT, 
intravesical instillations of a variety of chemotherapeutic agents have been tested in prospective 
randomized studies.  These studies are summarized in Table 1.  The agents have included 
thiotepa, mitomycin-C, epirubicin, doxorubicin, and epodyl.  While patients, drug dosages, times 
of instillation after TURBT, and durations of follow-up have varied, most studies have shown a 40 
- 50% reduction in tumor recurrences with active agents (see Table 1). 
 
 

 
S0337 
 
Page 7 
 
Version Date 10/29/13 
 
Table 1 
 
 
AGENT DOSE 
CONTROL 
# Pts 
STAGE 
NEW VS  
RECURRENT 
RECURRENCE 
RATE 2 YR 
MRC,  
Br J Urol 57:6810, 
1985 
Ttp 30 mg/50 ml 
vs obs 
256 
TaT1 
N only 
41.3%      35.4% p=.7 
MRC,  
Br J Urol 73:632, 
1994 
Long term f/u – 8.75 → no diff time to 1st recurrence, recurrence rate, or failure free 
interval 
Solsona, et al  
Br J Urol 161:1120, 
1999 
MMC 30mg/50ml 
NS vs obs 
121 
TaT1 
90% new 
10% recurrent 
RR 1yr 
22%        59% p<.005 
no diff in recurrences 
after 1 yr 
Oosterlinck, et al  
J Urol 149:749, 1993 
Epirub 80 mg in 
50cc NS vs 50 
ml H2O 
399 
TaT1 
80% new                  RR 1yr 
20% recurrent          17%      32% p<.0001 
                                10-15% 31% p<.0001 
                    Recurrent 26% 35% p = .38 
                    but after 12-18 mo 
recurrences  
                    were = & continued in each      
arm after 18 mo  4yr    
Burnand, et al 
Br J Urol 48:55, 1976 
Ttp 90 mg/100cc 
51 
TaT1 
Unknown 
Recurrences (2-5 yr 
f/u) 
57.9%* 96.8% p<.005 
*no recurrence at 
vault alone vs 21.9% 
at vault alone for 
control 
Ali-el-dein, et al 
Br J Urol 79:731, 
1997 
Epirub 50 
mg/50ml NS vs 
obs 
109 
(19% G3) 
TaT1 
55% new 
45% recurrent 
(24% interval to 
tumor recur) 
RR at mean 2.5 yr 
52%      p<.002 
16 mo   7 mo p<.05 
Rajala, et al 
J Urol 161:1133, 
1999 
Epirub 100 mg vs 
Ifα2b 50 M unit (3 
arm) vs obs 
200 
(12% G3) 
TaT1 
All new 
 
 
Single tumor 
Multiple tumors 
RR at 2 year 
Epi     Ifα    Cont 
32%  62% 60% p<.05 
27%  63% 55% 
56%  67% 74% 
Tolley, et al 
J Urol 155:1233, 
1996 
MMC 40 mg/40 
ml H2O vs obs 
306 
TaT1 
All new                     RR at 2 year 
                                 MMC      Cont 
                                 42%       55% p = .05 
After 18 mo no further improvement from 
MMC hazard rate MMC .66 control for 
recurrent 
Zincke, et al 
J Urol 129:505, 1983 
Ttp 60 mg/60ml 
Dox 50 mg/60ml 
H2O 60 ml 
45 
(roughly) 
Ta, T1, 
TIS 
21% new   
79% recur 
 
 
new 
recurrent 
RR at 3 mo – 4 mo 
Ttp      Dox       H2O 
30%    32%      71% 
43%    0           43% 
26%    38%      81% 
 
 
 
 

 
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In some studies, patients with newly diagnosed cancers were particularly advantaged, while in 
others those with recurrent tumors were advantaged.  (3,17)  The largest of the studies is that 
reported by Oosterlinck et al, carried out by the EORTC.  (3)  In this study, 80 mg of epirubicin in 
50 cc of saline was compared to 50 ml of sterile H20 immediately after TURBT of Stage Ta and 
T1 completely resected tumors in 399 patients.  Roughly 80% had new tumors and experienced a 
reduction of recurrence by over 50% from 31% recurrences per year in control patients to less 
than 15% in treated patients.  Patients whose index tumors were recurrent cancers experienced a 
non-significant reduction of recurrence rates compared to controls (p=.38).  The differences in 
recurrences were primarily achieved during the first 12 months, but these differences continued in 
each arm up to the four years of follow-up reported. 
 
Gemcitabine in Urothelial Cancer 
 
Gemcitabine 21, 21-difluoro-21-deoxycytidine is incorporated by dividing cells into DNA and will 
inhibit further DNA synthesis. It may also inhibit ribonucleotide reductase and cytidine deaminase 
activity.  (18)  This drug has been shown to be active against unresectable and metastatic cancers 
in several sites including bladder cancer.  In a variety of reports, single agent systemic 
gemcitabine for metastatic or unresectable TCC has had objective response rates ranging from 
22.5% to 28%.  (18)  When gemcitabine is used in "doublets" with cisplatin, carboplatin, or 
paclitaxel, response rate in the 24%-78% range, mostly 40% - 60% have been seen.  (17)  When 
used in "triplets" with cisplatin or carboplatin plus paclitaxel, objective response rates in Phase II 
studies have been in the 68% - 77% range.  (19)  Additionally, in a randomized prospective study 
of gemcitabine plus cisplatin versus methotrexate, vinblastine, adriamycin, cisplatin (MVAC) 
chemotherapy for unresectable or metastatic TCC, equivalence of the two regimens was found 
with less toxicity for the gemcitabine plus cisplatin arm.  (20)  Thus, this agent has efficacy both 
alone and in combination in advanced urothelial cancer.   
 
Intravesical Gemcitabine:  Based on these observations, Dalbagni and colleagues have in a 
Phase I study tested various concentrations of this agent in an intensive regimen (biweekly 
instillations for three weeks followed by a one week hiatus in which patients were cystoscoped, 
and then received three more weeks of biweekly instillations in dosages ranging from 500 to 2,000 
mg of gemcitabine in 100 ml of buffered water).  (21)  The 18 patients taking part in this Phase I 
study were at very high risk, having highly refractory TIS or more advanced superficial TCC.  
Thirty-nine percent of the patients achieved complete pathologic and cytologic responses and 
another 22% had mixed responses (negative biopsies but positive cytologies).   The responses 
were not clearly dose related when dosages of > 10 mg/ml were administered.  There was no 
response seen, however, at the lowest dose, 5 mg/ml.  At the 10 mg/ml dose, 3 of 6 patients 
experienced a complete response, 2 of 6 had a mixed response as defined above and 1 of 6 had 
persistent tumor.  Encouraged by these findings in an extremely high risk group of patients, 
Dalbagni, et al, are carrying out a Phase II trial of this regimen in highly refractory high risk 
superficial bladder cancer patients.   
 
Gemcitabine when dissolved in water or saline reduces the pH of the solution to the 2 to 3 range.  
Because at least in in vitro studies, acidification to this degree alone has toxic effects on human 
urothelial cells in culture, some authors have suggested buffering the solution with sodium 
bicarbonate to reach a pH of 5-6, which is physiologic in the bladder.  (O’Donnell, personal 
communication, (22) In the clinical study performed by Dalbagni, et al, such buffering was 
performed.  (21)  However, in no other studies (described below) has buffering been used. 
 
In a separate Phase I study, Laufer, et al, studied 15 patients with recurrent superficial bladder 
cancer (heavily pretreated with intravesical therapies) with six weekly instillations of gemcitabine 
dissolved in 0.9% saline beginning 2-4 weeks after TURBT.  (23)  Three patient cohorts were 
enrolled sequentially, receiving doses of 500, 1,000 and 1,500 mg in 100 ml 0.9% saline.  An 
additional six patients received 2,000 mg in 100 ml or 50 ml.  Nine of 13 evaluable patients had 
complete responses at six weeks after completion of therapy – all responders receiving ≥ 1,000  
 

 
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mg doses.  Pharmacokinetic studies demonstrated gemcitabine or its metabolite, 21 21 
difluorodeoxyuridure in plasma of patients transiently in doses ≥ 1,500 mg/100ml.  No Grade 4 
toxicities were seen but one patient receiving 2,000 mg/100 ml experienced reversible significant 
urinary frequency (stopped treatment).  While these patients received six weekly instillations, none 
were started for at least two weeks after TURBT.  Two other presentations of Phase I studies of 
escalating doses of gemcitabine in 50 ml 0.9% NaCl have been presented, using six weekly 
instillations starting 2-4 weeks after TURBT.  (24-25)  Each had a minimal intensity of side effects, 
primarily minor dysuria in 7 of 10 and 1 of 12 patients, respectively. 
 
Tolerability of Post TURBT Instillations of Gemcitabine 
 
Germane to the above comments, which are the rationale for this large proposed study, is that 
there have been several reports about tolerability of various dosages of gemcitabine.  In one study 
not yet reported, O’Donnell from the University of Iowa instilled immediate post-TURBT 
gemcitabine – five patients received 1,500mg/100ml 0.9% saline and five received 
2,000mg/100ml for 60 minutes.  Hematuria occurred in 2 of 10 and 10 of 10 respectively.  All 
other side effects were mild, transient, and unrelated to dose.  (22) 
 
In a separate study, Buettner and Boehle performed a small Phase I study of immediate post-
TURBT instillations of gemcitabine in dosages of 500 mg/50ml, 800 mg/50 ml, 1,000 mg/50 ml, 
1,000 mg/100 ml, 1,500 mg/100 ml and 2,000 mg/100 ml of 0.9% NaCl.  (26)  No systemic 
absorption of the drug was found for any of the dosages yet tested (based on pharmacokinetic 
data).  Moreover, all dosages were well tolerated except for 1,000 mg/50 ml which appeared to 
cause considerable bladder irritative symptoms that were relieved as soon as the fluid was 
drained from the bladder by unclamping the catheter.  Since this was not found at similar 
concentrations with higher volumes, even the authors are perplexed by these results.  Mild (Grade 
1 or 2) hematuria and/or dysuria that was quite transient were the only other side effects (in 9 of 
26 patients).  (26)  In addition, Maddineni and colleagues from the University of Manchester, 
England administered similar dosages of gemcitabine, again finding no systemic absorption in 15 
patients with frequently recurrent superficial bladder cancer.  They found the instillations to be 
quite tolerable, although at doses above 1,000 mg/ml dwell times exceeding 40 minutes became 
difficult to tolerate due to bladder spasms.  However these investigators were choosing 20 - 24 
hours post TURBT for instillations, not three hours when anesthetic effects are likely to permit 
greater drug retention.  Ten of the 15 patients have been evaluated for recurrence, five of whom 
were tumor free.  (27) 
 
In a separate study, Palou, et al, treated five patients each with 1,500 or 2,000 mg/100 ml 0.9% 
NaCl, within three hours of TURBT.  No significant toxicities were seen, with only one patient at 
the 2,000 mg dose experiencing only self-limited minor urinary irritation and two patients at the 
1,500 mg dose experiencing transient Grade 1 hypogastric discomfort.  (28)  Mean maximum 
serum concentrations of gemcitabine were 1.8 ug/ml, and no systemic toxicity was seen.  Four of 
the ten patients were found to have recurrences on reevaluation.  A summary of these pilot data 
on intravesical gemcitabine appear in Table 2. 
 
 
 

 
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Table 2. 
Phase I Clinical Experience 
 
 
 
Reference 
 
Number 
of 
Patients 
 
Gemci-
tabine 
Dose 
(mg) 
Dilution 
(Normal 
Saline) 
(mL) 
 
Dwell 
Time 
(hr) 
 
Dosing 
Schedule 
 
 
Buffering 
Grade 3/4 
Systemic 
Toxicity 
(Patients) 
Dalbagni,  
et al, 2002 
18 
500-
2000 
100 
1  
Twice 
weekly 
Yes 
2* 
 
 
 
 
 
 
 
 
Laufer, 
et al, 2003 
15 
500-
2000 
50-100 
2 
1x week 
No 
0 
 
 
 
 
 
 
 
 
Witjes,  
et al, 2004 
10 
1000-
2000 
50 
1 
1x week 
No 
0 
 
 
 
 
 
 
 
 
DeBerardinis,  
et al, 2004 
12 
500-
2000 
50 
2 
1x week 
No 
0 
 
 
 
 
 
 
 
 
Buettner, et al, 
2003 
 
26 
500-
2000 
50-100 
0.5  
Single 
dose 
adjuvant 
No 
0 
 
 
 
 
 
 
 
 
Palou,  
et al, 2004 
10 
1500-
2000 
100 
1  
Single 
dose 
adjuvant 
No 
0 
 
 
 
 
 
 
 
 
Maddineni,  
et al, 2003 
15 
500-
1000 
100 
1-2  
Single 
dose 
adjuvant 
No 
0 
* One Grade 3 neutropenia and thrombocytopenia was reported at the 2,000 mg level, and one 
Grade 3 "hand/foot syndrome" was reported at the 1,000 mg level. 
 
Proposed Clinical Trial – Efficacy and Morbidity of Therapy: 
 
Reducing the recurrence rate of superficial bladder cancer has benefit in terms of reduced 
morbidity and expense, and possibly reduces serious morbidity and mortality.  Immediate post-
transurethral resection (TUR) instillation therapy is standard treatment in Europe, but has not 
been popular in North America.  The publication of a North American study showing efficacy is 
likely to change practices of North American urologists.  The use of gemcitabine will not only 
confirm the benefits of post TURBT instillation therapy, but also will test the efficacy of this agent, 
which has promising effects against high risk urothelial cancer in topical and systemic 
applications. Since this is preventing recurrence in a somewhat mixed group of patients whose 
composite populations have a range of recurrence rates, designs other than randomized 
prospective trials have no realistic chance of establishing efficacy, and use of saline control is 
valuable to make certain that active agent is more efficacious than diluent alone. We propose to 
determine if gemcitabine in a dosage and volume that appear to be well tolerated (2,000 mg in 
100 ml of 0.9% NaCl) when instilled intravesically immediately after TURBT (within 3 hours), is 
more effective than instillation of sterile saline in preventing recurrences of newly diagnosed or 
occasionally recurrent low grade superficial bladder cancer that has been endoscopically resected 
in its entirety.  Additionally, by preventing short-term recurrences, we believe this therapy will also 
reduce longer term recurrences, and the need for frequent TURBTs, more traditional courses of 
intravesical therapy, and very frequent surveillance cystoscopies.   
 
 
 

 
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Proposed Correlative Studies: 
 
The follow-up of patients with superficial bladder cancer is a subject of great interest because of 
the inconvenience, expense and morbidity of frequent cystoscopies.  Use of a non-invasive 
technique which has equal accuracy to cystoscopy would be desirable, but currently no 
commercially available noninvasive test is believed to have sufficient sensitivity in itself to replace 
cystoscopy.  In this study, two commercially available, point-of-care, non-invasive tests will be 
used in addition to cystoscopy to see if any, alone or in combination, can equal the sensitivity of a 
cystoscopy.  This will provide compelling information on each test (data on combined tests are not 
available) and are likely, if a positive result is found, to significantly change standard urologic 
practice. Additionally, this will provide necessary background information for a bladder cancer 
screening trial which may be proposed in the future. 
 
Summary 
 
In summary, we propose that immediate (within three hours) post TURBT intravesical gemcitabine 
will significantly improve the recurrence free survival occurring with intravesical saline, from 40% 
(with saline) to 55% (with gemcitabine) at two years post TURBT in patients with newly diagnosed 
or occasionally recurrent Grade 1 or 2, Ta or T1 bladder cancer that has been endoscopically 
resected in its visible entirety. 
 
Inclusion of Women and Minorities: 
 
Women and Minorities 
 
Based on a previous Southwest Oncology Group superficial bladder cancer trial, the expected 
breakdown by race and sex would be: 
 
 
White  
Black 
Asian/Pacific 
Islander 
Native 
American 
Total 
Male  
289 
7 
1 
0 
297 
Female 
40 
3 
0 
0 
43 
Total 
329 
10 
1 
0 
340 
 
Treatment interactions are not anticipated, so the trial has not been powered to address specific 
race or gender questions.  However, we will do exploratory analyses of treatment by race and 
treatment by gender interactions at the end of the study. 
 
 
3.0 
DRUG INFORMATION 
 
3.1 
Gemcitabine hydrochloride (Gemzar®) (NSC-613327) (IND-73,058) 
 
a. 
DESCRIPTION 
 
2'-Deoxy-2', 2'-difluorocytidine monohydrochloride (Gemcitabine hydrochloride or 
Gemcitabine®) is a white to off-white or translucent solid with a molecular weight 
of 299.66. 
 
Mechanism of Action:  Gemcitabine, like ara-C, is an analog of deoxycytidine.  
This antimetabolite, a pyrimidine analog inhibiting both DNA and RNA viruses, is 
cell-cycle-specific in blocking the cells at the G1/S and is retained in human tumor 
cells for long periods.  Studies suggest that gemcitabine is activated by 
deoxycytidine kinase.  Deoxycytidine has been shown to reverse the growth 
inhibitory activity of gemcitabine. 
 
 

 
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b. 
TOXICOLOGY 
 
Human Toxicology:  Phase I clinical experiences with intravesical gemcitabine 
have been reported in seven studies where dose ranges of 500 to 2,000 mg at 
concentration of 20 - 40 mg/ml with 1 to 2 hours of indwelling time were used. 
Four of these studies were performed in patients who had intact bladder mucosa.  
The most common side effects reported were urinary frequency and hematuria. 
At 2,000 mg dose level, Grade 3 urinary frequency and local irritation were the 
most common complaints.  (21,23,25)  Grade 3 thrombocytopenia and 
neutropenia without infection was reported in one out of six patients.  (21)  The 
remaining three Phase I studies were performed in patients immediately after, 
within three hours after, and up to 24 hours after transurethral resection.  (26-28)  
No additional adverse events were noted in these patients.  A few cases of renal 
failure of uncertain etiology have been reported with intravenous gemcitabine 
administration.  While on study, one patient who received prior mitomycin 
developed hemolytic uremic syndrome requiring dialysis.  The relationship of this 
event to intravenous gemcitabine is not known. 
 
Pregnancy and Lactation:  Gemcitabine may cause fetal harm when administered 
to a pregnant woman.  This agent has produced teratogenic effects in mice and 
rabbits when administered at a dose of < 2 mg/m2.  Adverse effects included 
decreased fetal viability, weight and morphologic defects.  There is no data on 
gemcitabine administration during human pregnancy, and it is not currently known 
if metabolites are excreted in human milk.  However, many drugs are excreted in 
human milk, and there is a potential for adverse effects in nursing infants.  
Therefore, the use of gemcitabine should be avoided in pregnant or nursing 
women because of the potential hazard to the fetus or infant. 
 
c. 
PHARMACOLOGY 
 
Kinetics:  Gemcitabine is metabolized intracellularly to form active gemcitabine di- 
and tri-phosphates.  Additional metabolites have not been identified in either 
plasma or urine.  The gemcitabine di- and tri-phosphates do not appear to 
circulate in plasma in measurable amounts.  The compound is metabolized 
principally by the liver to form an inactive uridine derivative (dFdU or 2'-deoxy-
2',2'-difluorouridine).  The plasma protein binding of gemcitabine is negligible.  
Following a single 1,000 mg/m2/30 min [14C]-gemcitabine infusion, 92% to 98% of 
the dose was recovered within one week after gemcitabine administration.  
Urinary excretion of parent and dFdU accounted for 99% of the excreted dose, 
and less than 1% of the dose was excreted in feces.  The renal clearance of 
gemcitabine is less than 10%; therefore, the parent drug appears to be almost 
completely metabolized to the inactive dFdU. 
 
Half-life ranged from 11 to 26 minutes for patients receiving single dose infusions 
(1,000 mg/m2 to 2,500 mg/m2) of 1.1 hours or less.  Following longer duration 
infusions (3.6 to 4.3 hours), the half-life ranged between 18.5 and 57.1 minutes 
for single gemcitabine doses between 2,500 mg/m2 and 3,600 mg/m2.  The 
increase in half-life may relate to the appearance of a possible third exponential 
phase (representing a deep compartment) that is not observed following the 
shorter infusions. 
 
The population pharmacokinetic analyses of the effect of patient specific 
characteristics showed that clearance normalized for BSA was affected by 
gender.  The clearance obtained for the female patient for all studies was 46.2 
L/hr/m2 and the male's was 66.8 L/hr/m2.  These moderate to high gemcitabine 
values suggest that gemcitabine may be metabolized by various tissues, including 
the liver.  The renal clearance for gemcitabine is less than 10% of the systemic 
clearance.   
 

 
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The maximum dFdU plasma concentrations were achieved from 0 to 30 minutes 
after the discontinuation of the gemcitabine infusions, ranging from 0.4 to 4.75 
hours.  The apparent formation of dFdU (determined from the fraction of the 
gemcitabine dose excreted as dFdU) ranged from 91.2% to 98.2% of 
gemcitabine clearance in a single-dose study.  Based on the imputed formation 
rate of dFdU, the mean dFdU volume of distribution at steady-state was 150.4 
L/m2, indicating that dFdU was extensively distributed into tissues.  The 
metabolite was excreted in urine without undergoing further biotransformation.  
The mean apparent clearance of dFdU was 2.5 L/hr/m2. 
 
Pharmacokinetics (PK) of intravesical gemcitabine and its metabolite, dFdU, were 
studied in plasma and urine by Laufer, et al.  (23)  Plasma samples for PK were 
collected before the instillation and 15, 30, 60, 90, and 120 minutes after the 
instillation.  Gemcitabine was observed in plasma of the 4 patients treated with 40 
mg/mL in 50 mL normal saline, but not in the patients treated with 20 mg/mL in 
100 mL normal saline.  Peak concentrations in this and several other studies 
were below 1 µg/mL, which were significantly lower than the 10 to 30 µg/mL 
observed after a single intravenous (IV) dose of 1,000 mg/m2 (Lilly 2002).  The 
plasma gemcitabine concentrations declined rapidly, even during the 120-minute 
dwell time, and no gemcitabine was detectable in patient plasma beyond 60 
minutes after the instillation of the drug.  DFdU was also not detected in patients 
treated with 500 or 1,000 mg of gemcitabine.  In the 1,500 mg and 2,000 mg 
groups, plasma concentrations of dFdU increased progressively during the first 
60 to 90 minutes of dwell time, after which they remained constant during the 
observation period. 
 
The authors estimated that based on their PK results and the 120-minute dwell 
time, the predicted amounts of gemcitabine absorbed from the bladder ranged 
from 10 to 110 mg, corresponding to 0.52% to 5.52% of the total gemcitabine 
dose instilled.  No dFdU was measured in voided urine, and 61% to 100% of the 
gemcitabine was accounted for in the voided urine.  The authors also studied the 
in vitro decomposition at 37°C with gemcitabine incubated with three control urine 
samples.  They found no reduction in the concentration of gemcitabine, nor was 
any production of dFdU observed.  Minimal systemic absorption based on 
measured 
serum 
gemcitabine 
levels 
following 
intravesical 
gemcitabine 
administration was confirmed by the other six Phase I studies.  (21,24-28) 
 
Formulation; Storage and Stability; and Reconstitution:  Gemcitabine is supplied 
as a lyophilized powder in sterile vials containing 1,000 mg of gemcitabine as the 
hydrochloride salt (expressed as the free base), mannitol, and sodium acetate.  
The lyophilized product should be stored below 30°C.   
 
The drug will be reconstituted with 25 mL of 0.9% Sodium Chloride Injection to 
the 1 gram vial.  The vial will be shaken to dissolve.  This dilution yields a 
gemcitabine concentration of 38 mg/mL which includes accounting for the 
displacement volume of the lyophilized powder (1.3 mL for the 1 gram vial). The 
total volume upon reconstitution will be 26.3 mL.  Complete withdrawal of the vial 
contents will provide 1 gram of gemcitabine.  The procedure will be repeated with 
a second 1 gram vial to reach the 2 gram dose for treatment.  The appropriate 
amount of drug may be administered as prepared or further diluted with 0.9% 
Sodium Chloride Injection  to concentrations as low as 0.1 mg/mL.  For this trial, 
gemcitabine will be reconstituted according to above guidelines and the 2 gram 
treatment dose volume (approximately 52.6mL) will be loaded into a syringe and 
additional 0.9% Sodium Chloride for injection will be added to reach a 100 mL 
volume.  Rationale for the 100 mL volume is addressed in Section 2.0 of the 
protocol. 
 
 

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Revised 10/21/09 
 
Control drug will consist of 0.9% sodium chloride solution.  Since it is not possible 
to use a placebo powder in intravesical therapy without inadvertent alteration of 
the bladder epithelium, the pharmacist will be unblinded in this trial. 
 
Reconstituted gemcitabine is a clear, colorless to light straw-colored solution.  
After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting 
solution lies in the range of 2.7 to 3.3.  The solution should be inspected visually 
for particulate matter and discoloration, prior to administration, whenever solution 
or container permits.  If particulate matter or discoloration is found, do not 
administer.  When prepared as directed, gemcitabine solutions are stable for 24 
hours at controlled room temperature 20° to 25°C (68° to 77°F) [See USP].  
Unused portions will be discarded.  Solutions of reconstituted gemcitabine should 
not be refrigerated, as crystallization may occur. 
 
Administration:  Intravesical. 
 
Handling Precautions:  Gemcitabine is a toxic material which could cause skin 
and eye irritation.  Ingestion or inhalation exposure of sufficient quantities could 
result in decreased white and red blood cells, hypospermatogenesis, 
gastrointestinal disturbances, and other signs of toxicity.  The compound was 
positive in one of three tests for mutagenicity.  Laboratory animal studies indicate 
that compounds in this therapeutic class may be reproductive toxins and may 
induce fetal malformations.  Contact or inhalation should be avoided.  The urine 
and solution drained after the foley catheter is unclamped should be discarded as 
hazardous waste according to local, state and federal policies. 
 
Supplier:  Gemcitabine is considered investigational for this study and will be 
supplied by Lilly.  The study drug will be distributed by Pharmagistics.  
Pharmagistics will be notified automatically after each new randomization.  Study 
drug and a letter outlining the treatment preparation will be shipped via overnight 
delivery to the pharmacist to arrive within 2 business days.  For patients 
registered Monday through Thursday prior to 2 p.m. Eastern time, drug will be 
delivered the next day.  For patients registered Friday through Sunday, or on a 
holiday, drug will be shipped the next business day for arrival the following day.  
For patients registered Thursday after 2:00 p.m. Eastern time or Friday prior to 
2:00 p.m. Eastern time, shipment on Friday for Saturday delivery may be 
arranged only if the pharmacy is prepared to receive shipment on Saturday.  If 
Saturday delivery is required, this MUST be communicated to Bryan Goldman 
(bgoldman@fhcrc.org) or in his absence Cathy Tangen (ctangen@fhcrc.org) at 
the Southwest Oncology Group Statistical center PRIOR to registration.  Each 
investigator MUST be linked to an active pharmacy in the SWOG database. 
 
Important:  you must record the patient identification number, which is assigned 
at the time of randomization, for each patient you register.  Your pharmacist will 
need this patient number in order to identify the appropriate package from the 
drug distributor for each of your patients. 
 
Emergency Unblinding:  See Appendix 18.2 for emergency unblinding 
instructions. 
 
 
 

 
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4.0 
STAGING CRITERIA (AJCC Sixth Edition, 2002) 
 
BLADDER PRIMARY TUMOR (T) 
 
Ta 
Non-invasive papillary carcinoma. 
 
T1 
Tumor invades subepithelial connective tissue. 
 
HISTOPATHOLOGIC TYPE 
 
The histologic types are:  Urothelial  (transitional cell) carcinoma. 
 
HISTOPATHOLOGIC GRADE (G) 
 
Grade 1 
Well differentiated (papillary urothelial tumor of low malignant potential). 
 
Grade 2 Moderately differentiated (low grade urothelial cancer). 
 
 
 

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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 Prestudy Form and submit to the Data Operations 
Center in Seattle (see Section 14.0).   Any potential eligibility issues should be addressed to the Data 
Operations Center in Seattle at 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 one week later would be considered Day 7.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 7, 28, 56, 145 or 365 falls 
on a weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must: 
 
• 
clinically appear to have newly diagnosed or recurrent Grade 1 or 2, Ta or T1 
urothelial (transitional cell) cancer of the bladder, 
• 
have had no more than 2 recurrences (other than the index tumor) in the 18 
months preceding the index tumor's TURBT which are also Grade 1 or 2, 
Stage Ta or T1 without any previous TIS or Grade 3 cancers within 2 years 
preceding the index tumor TURBT or any history of muscularis propria 
invading (Stage ≥ T2), 
• 
in their urologist's opinion not currently be a candidate for treatment other 
than a TURBT (e.g., a series of BCG instillations). 
 
Central pathology review is not required. 
 
5.2 
Prior Therapy Criteria 
 
a. 
There must be plans for the patient to receive a TURBT within 28 working days 
after randomization.  There must be plans for treatment to be given within three 
hours of TURBT. 
 
b. 
Patients must not have received previous intravesical therapy within 145 days 
prior to registration.  Patients must not be considered by their treating physician to 
be candidates for more intensive treatments such as a series of instillations of 
intravesical immunotherapy (e.g. BCG) or intravesical chemotherapy, or for 
cystectomy or partial cystectomy. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have a negative urine culture (including ≤ 10,000 col/ml or "mixed 
flora-likely contamination") or a negative urine analysis for infection with (either a 
microscopic urinalysis with negative nitrates and no organisms on reagent strip 
and < 10 wbc/hpf OR an automated or visual reagent strip urinalysis which is 
negative for leukocytes and nitrates) within 28 days prior to registration. 
 
b. 
Patients must have a Zubrod performance status of 0 - 1 (see Section 10.5). 
 
 
 

 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
(5.3 Clinical/Laboratory Criteria contd.) 
 
c. 
Patients must not be pregnant or nursing.  Women/men of reproductive potential 
must have agreed to use an effective contraceptive method. 
 
d. 
Except as outlined in Section 5.1, 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 3 years. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must be offered the opportunity to participate in specimen banking as 
outlined in Section 15.0 of the protocol. 
 
5.5 
Regulatory Criteria 
 
a. 
All patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
At the time of patient registration, the treating institution's name and ID number 
must be provided to the Data Operations Center in Seattle in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered into the data base. 
 
 
 
 
 
 

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6.0 
STRATIFICATION FACTORS 
 
Patients will be centrally randomized at the Southwest Oncology Group Statistical Center.  At the 
time of registration, patients will be randomly assigned to either Arm 1 or Arm 2 in a blinded 
fashion according to a dynamic allocation scheme.  (29)  The treatment arms will be balanced 
with respect to the following factors: 
 
a. 
Disease status:  first occurrence versus recurrent disease,  
 
b. 
One tumor site versus two or more tumor sites. 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification-related questions, please contact Dr. Edward M. Messing at 
585/275-3345 or Dr. David P. Wood, Jr. at 248/551-0678.  For dosing principles or questions, 
please consult the Southwest Oncology Group 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 
Good Medical Practice 
 
The following pre-study tests should be obtained within 28 days prior to registration in 
accordance with good medical practice.  Results of these tests do not determine eligibility 
and minor deviations would be acceptable if they do not impact on patient safety in the 
clinical judgment of the treating physician.  The Study Chair must be contacted if there are 
significant deviations in the values of these tests. 
 
a. 
WBC ≥ 3,000/mcL, 
 
b. 
Hematocrit > 35 and < 52 and Hemoglobin > 10 and < 16, 
 
c. 
Serum creatinine < 2.2 mg%, 
 
d. 
Platelet count > 75,000/mcL and < 500,000/mcL, 
 
e. 
SGOT or SGPT, Alkaline phosphatase, and total bilirubin ≤ 2 x institutional upper 
limit of normal. 
 
f. 
Patients should be believed based upon endoscopic inspection not to have 
urothelial cancer of the prostate or more distal urethra (or urethra at all in 
women).  Endoscopy should be performed within 56 days prior to registration. 
 
g. 
Patients should have negative upper tract imaging studies obtained within 365 
days prior to registration.  Imaging studies may be performed after registration, 
but prior to TURBT on the day of treatment. 
 
7.2 
Treatment 
 
Within 28 working days after randomization, patient will have a complete resection of all 
visible index bladder tumors (TURBT).  The investigator, treating urologist and patient will 
be blinded to treatment, but the local institutional pharmacist will not. 
 
Patients will be randomized to one of two treatment groups. 
 
 

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Arm 1 - Within three hours following complete TURBT of index tumor(s) patients will 
receive intravesical gemcitabine – 2,000 mg in 100 ml of 0.9% NaCl. Solution is to be held 
in the bladder for one hour by clamping foley catheter.  If this is not tolerable based on 
pain or other signs or symptoms, the duration of time held, and reason for premature 
release must be reported on the S0337 Treatment Summary Form. After one hour, the 
catheter will be unclamped and allowed to drain. Irrigation of the bladder will not be 
performed immediately after unclamping (unless as is clinically indicated to assure 
catheter patency). 
 
Arm 2-within 3 hours following complete TURBT of index tumor(s), patients will receive 
100 ml of sterile 0.9% NaCl. Solution is to be held in the bladder for one hour by clamping 
foley catheter. If this is not tolerable based on pain or other signs or symptoms, the 
duration of time held, and reason for premature release must be reported on the S0337 
Treatment Summary Form.  After one hour, the catheter will be unclamped and allowed to 
drain. Irrigation of the bladder will not be performed immediately after unclamping (unless 
as is clinically indicated to assure catheter patency). 
 
For both groups, if immediate post TURBT bleeding is considered too brisk by the treating 
urologist to permit catheter clamping and intravesical instillation of study drug, continuous 
or intermittent irrigation via a 3-way catheter of 0.9% NaCl or sterile water is permitted up 
to 3 hours post operatively. 
 
Patients will be followed with cystoscopies every three months for two years and then 
every 6 months for an additional two years.  Positive cystoscopies should be biopsied and 
pathology reports submitted to the Data Operations Center.  Tissue from the first positive 
biopsy should be submitted per Section 15.0 if the patient has consented. 
 
Because non-malignant lesions can be mistaken for recurrence, suspected recurrences 
must be biopsied. 
 
7.3 
NMP-22 Bladder Chek and BTA Stat Testing 
 
Urine samples will be collected pre-treatment and then every three months for two years 
for NMP-22 Bladder Chek and BTA Stat testing.  These tests are commercially available 
and the tests must be performed at the local site and the results reported to the Data 
Operations Center in Seattle on the S0337 Cystoscopy and Urine Markers Form.  
Instructions for sample processing are included in each of the tests. 
 
7.4 
Criteria for Removal from Protocol Treatment 
 
a. 
Completion of intravesical instillation. 
 
b. 
Unacceptable toxicity - however, patients will be analyzed for outcome and 
toxicity even if the instillation is ended in less than 1 hour because of side 
effects/intolerability. 
 
c. 
Delay of instillation more than three hours post-TURBT. 
 
d. 
Urologist believes at the end of the TURBT, because of depth of tumor resection, 
degree of bleeding, medical instability, etc. that instillation is contraindicated. 
 
e. 
The patient may withdraw from the study at any time for any reason. 
 
7.5 
Emergency Unblinding 
 
Procedures for emergency unblinding of the gemcitabine/saline treatment assignment are 
outlined in Appendix 18.2. 
 

 
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7.6 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the study forms. 
 
7.7 
Follow Up Period 
 
All patients will be followed for a maximum of 4 years after registration. 
 
 
8.0 
DOSAGE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events. 
 
Two different versions of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 
will be utilized for SAE reporting only.  The CTCAE Version 4.0 is identified and 
located at the CTEP website at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 
4.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 3.0 for routine toxicity reporting.  A copy 
of the CTCAE Version 3.0 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 3.0. 
 
8.2 
General Dose Modification Considerations 
 
a. 
There will be no dose modifications.  Duration of retention of drug/control can be 
shortened if medically indicated (e.g. bleeding, pain or bladder spasm 
uncontrollable by symptomatic medications, feared bladder perforation, etc.). 
 
b. 
Toxicity measurements include a CBC.  This will be done somewhere between 7 
and 14 days post instillation.  If white blood count is below 3,000/mcL or platelet 
below 75,000/mcL, these tests must be repeated at least on a weekly basis until 
they reach pre-treatment levels. 
 
8.3 
Gemcitabine Dose Modifications. 
 
a. 
Pulmonary toxicity:  If pneumonitis Grade 2 or higher develops and is related to 
gemcitabine, gemcitabine should be promptly discontinued and the patient should 
be removed from protocol treatment.  Treatment with corticosteroids should be 
given according to established guidelines. 
 
b. 
Hemolytic uremic syndrome (HUS) toxicity:  The diagnosis of hemolytic uremic 
syndrome should be considered if the patient develops anemia with evidence of 
microangiopathic hemolysis as indicated by elevation of bilirubin or LDH, 
reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure  
 

 
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Revised 8/29/13 
 
(elevation of serum creatinine of BUN).  Gemcitabine therapy should be 
discontinued immediately.  Renal failure may not be reversible even with 
discontinuation of therapy and dialysis may be required. 
 
8.4 
Dose Modification Contacts 
 
 
 
For treatment or dose modification related questions, please contact Dr. Edward M. 
Messing at 585/275-3345 or Dr. David P. Wood, Jr. at 248/551-0678. 
 
8.5 
Adverse Event reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via AdEERS, and to the IRB per local IRB requirements. 
 
 
 
 

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Version Date 10/29/13 
 
9.0 
STUDY CALENDAR 
REQUIRED STUDIES 
PRE 
PRE 
Wk 
Wk 
Wk 
Wk 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
  
STUDY 
TREATMENT 
1 
2 
3 
4 
3 
6 
9 
12 
15 
18 
21 
24 
30 
36 
42 
48 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and Physical Exam 
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and Performance 
Status 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Disease  Assessment    
X¥ 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Notation    £ 
  
  
X 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
LABORATORY   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC/Differential/Platelets å 
X 
  
  
Xµ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum Creatinine  å 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine Analysis 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SGOT/SGPT  å 
X 
  
  
Xµ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Alkaline Phosphatase  å 
X 
  
  
Xµ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bilirubin  å 
X 
  
  
Xµ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
NMP-22 Bladder Check 
  
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
BTA Stat 
  
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
OPTIONAL SPECIMEN 
SAMPLES (BANKING) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tissue   
(see Section 15.1) Ω 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Whole blood   
(see Section 15.2) 
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
X-RAYS & SCANS  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IVP for Retrogrades or CT 
with IV Contrast   
X¥  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cystoscopy  ¶ 
X 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TURBT & Blinded 
Treatment 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Click here for Footnotes. 
 
 

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S0337 
 
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Note:  Forms submission guidelines are found in Section 14.0. 
 
Footnotes 
 
å  These tests are suggested  prestudy for Good Medical Practice (see Section 7.1), but are required during treatment and follow-up as indicated  
 
above, or more frequently as clinically indicated. 
¥   To be performed within 6 months before registration.  
¶   Histologic confirmation of recurrence required.  
µ   CBC/Platelets must be obtained between 7 and 14 days post instillation.  Blood counts may be performed more often at the discretion of the  
 
treating investigator.  If cytopenias or liver function test abnormalities are observed, patients should be followed weekly until these laboratory 
 
test abnormalities have resolved. 
Ω  With the patient's additional consent, it is strongly recommended that tissue be submitted per Section 15.1 from TURBT and at time of first  
 
recurrence and/or progression. 
£  
A toxicity assessment should be made 7-14 days after the TURBT.  Only if adverse events are noted during this earlier period (Week 1-2)  
 
should a Week 4 assessment also be done. 
 
 
 
 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Recurrence 
 
Histological confirmation of recurrence is required.  Cystoscopic and cytologic evidence 
alone is not satisfactory – although will be noted. 
 
10.2 
Time to Recurrence 
 
From date of registration to date of first observation of recurrent disease subsequently 
confirmed by biopsy.  Patients without recurrence are censored at the time of their last 
cystoscopy. 
 
10.3 
Progression 
 
Recurrence of urothelial cancer to Stage ≥ T2, or other diagnosis of N+ or M+ disease. 
 
10.4 
Time to Progression   
 
From date of registration to date of diagnosis of progressive disease.  Censor at date of 
last disease assessment for those without progression. 
 
10.5 
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.   
 
10.6 
Worsening-free Survival   
 
From date of registration to date of first observation of subsequently confirmed recurrent 
disease (as defined in Section 10.2), progression (as defined in Section 10.3), start of 
systemic chemotherapy, radiation or cystectomy, or death due to any cause.  Patients who 
experience none of these events will be censored at date of last disease assessment. 
 
10.7 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
 
 

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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Primary Endpoint 
 
The primary objective of this study is to compare the efficacy of a single post-TURBT 
intravesical instillation of gemcitabine versus saline in preventing recurrence of completely 
resected Grade 1 or Grade 2, Ta or T1 transitional cell carcinoma of the bladder.  The 
endpoint of interest is time to recurrence which is defined (see Section 10.2) as time from 
date of registration to date of first observation of recurrent disease subsequently 
confirmed by biopsy.  Those without recurrence are censored at the date of last 
cystoscopy.  Patients who die without any evidence of disease recurrence, will be 
censored at time of death. 
 
If one assumes roughly equal numbers of patients with newly diagnosed and recurrent 
superficial bladder tumors, then we anticipate about 60% of patients will experience 
recurrences by 2 years.  It is assumed that 14 eligible patients per month will be 
randomized.  Patients will be stratified by disease status (first occurrence vs. recurrent 
disease), and number of tumors (one versus more than one).  Assuming exponential 
time-to-recurrence (TTR) and 60% TTR (40% recurrence-free) at two years in the sterile 
saline group, then two years of accrual (340 eligible patients) and two additional years of 
follow-up will be required for a one-sided 0.025 level test to have power 0.89 for detecting 
a hazard ratio of 1.53 (equivalent to an improvement to a 45% TTR (55% recurrence-free) 
rate at two years on the gemcitabine arm).  The primary test will be performed using the 
stratified logrank test.  All eligible, randomized patients will be used in the primary analysis 
regardless of whether they actually receive the treatment to which they were assigned 
(intent-to-treat analysis). 
 
Estimate of sample size:  340 eligible 
Estimate of accrual rate:  170 eligible/year 
 
Two interim analyses of time-to-recurrence will be performed after 50% and 80% of the 
expected number of events have occurred (113 and 181 relapses, respectively, assuming 
the alternative treatment hypothesis) which will be approximately at the time accrual is 
completed and one year later.  Consideration will be given to reporting early at either time 
if (1) TTR on the gemcitabine arm is superior at the one-sided 0.005 level or if (2) the 
hypothesis λ=1.53 (where λ is the sterile water/gemcitabine hazard ratio) is rejected in 
favor of λ<1.53 at the one-sided 0.005 level (testing using a proportional hazards score 
test, an extension of the logrank test).   
 
Assuming the study does not terminate early and the alternative treatment hypothesis, the 
final analysis will occur when approximately 226 recurrences have been reported 
(estimated to be about two years after completion of accrual).  The final analysis will be 
based on the stratified logrank test with stratification factors as specified in Section 6.0 
with a one-sided 0.020 level to adjust for the two interim analyses, for an overall level of 
0.025 (one-sided).  In addition, the trial will be monitored for safety every six months and 
assuming the alternative hypothesis holds. 
 
11.2 
Secondary Endpoints 
 
A sample of 170 patients per arm is sufficient to estimate the probability of a specific 
toxicity to within at worst = ± 0.077.  There is power of 0.81 for a one-sided 0.025 level 
test to detect a 0.16 difference in a specific toxicity probability between the two arms. 
 
The logrank test will be used to evaluate whether worsening-free survival (see Section 
10.0 for definition) is better on the gemcitabine arm relative to the saline arm.  Descriptive 
statistics will be used to evaluate the number of diagnostic tests required for individuals 
on each treatment arm.  
 

 
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11.3 
Sensitivity and Specificity of Assays for Predicting Recurrence 
 
Sensitivity and specificity of the BTA Stat and the NMP-22 Bladder Chek alone and in 
combination are the primary endpoints of this correlative study.  The gold standard to 
define a recurrence is a positive biopsy prompted by a cystoscopy.  Absence of 
recurrence will be confirmed by a negative complete diagnostic work-up.  Disease status 
will be evaluated every three months for two years and then every six months for an 
additional two years.  Recurrence information over time is not independent within an 
individual.  To account for this correlation, a GEE approach will be used to estimate 
sensitivity and specificity.  GEE accounts for correlation within participants when 
estimating parameters and the corresponding standard errors are adjusted.  Logistic 
regression using general estimating equation methodology (to account for repeated 
evaluations of an individual) will be used to assess and compare sensitivity and specificity 
of accurately classifying recurrence status using information from each individual urinary 
marker. 
 
The BTA Stat test and the NMP-22 Bladder Chek test will have responses positive, 
negative or invalid.  Invalid tests at a given time will not be used in the GEE analyses.  
Two types of analyses will be performed using these urine markers.   
 
The following information was obtained from the Early Detection Research Network 
(EDRN) protocol entitled, “Detection of bladder cancer by microsatellite analysis of urinary 
sediment:  Multi-Institutional Study, Version 1.5” with Mark Schoenberg, M.D. as the 
Study Chair and Mark Thornquist, Ph.D., as the study statistician. 
 
In that EDRN study, they assumed that 270 patients will have follow-up data, and 81 of 
the 270 would have a recurrence during the two year surveillance period.  Those numbers 
are lower than the 300 patients and 120 recurrences that we would expect during the 
same period if we assume 10% loss to follow-up and a 40% recurrence rate at two years.  
So the estimates that they simulated would be expected to be conservative. 
 
They generated 250 datasets for each sensitivity and specificity pair.  The data are 
summarized by looking at the distribution of sensitivities and specificities.  The table 
below shows the result when the simulations assumed exchangeable correlation between 
observations within a patients. 
 
Table from Section 7.2 of EDRN Superficial Bladder Protocol: Simulations 
 
Sensitivity 
Specificity 
Std Error 
Sensitivity 
Std Error 
Specificity 
95% CI 
Sensitivity 
95% CI 
Specificity 
0.95 
0.95 
0.020 
0.005 
0.89, 0.97 
0.94, 0.96 
0.90 
0.90 
0.028 
0.007 
0.81, 0.92 
0.89, 0.91 
0.85 
0.85 
0.033 
0.009 
0.75, 0.88 
0.83, 0.86 
0.80 
0.80 
0.035 
0.010 
0.70, 0.82 
0.78, 0.82 
 
This table shows that the EDRN study, with a slightly smaller sample size and lower 
expected event rate, will have ample power to detect relevant values of sensitivity and 
specificity while ruling out unacceptable low values.  We, therefore, would expect S0337 
to have at least as much power if not more to estimate the properties of the BTA Stat and 
NMP-22 urine markers individually and in combination.   
 
 

 
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a. 
Surveillance estimates of sensitivity and specificity 
 
These analyses will evaluate the performance of each of the markers, alone and 
in combination, every three months for the first two years of the study. At each 
follow-up time t, cases will be those who are biopsy positive at time t, and controls 
will be those with negative cystoscopy exams or positive cystoscopy exams but 
biopsy-negative.  All patients will have a cystoscopy every three months, 
regardless of urine marker results. 
 
Sensitivity and specificity will be defined based on the concurrent marker status. 
 
M+ = positive marker 
M - = negative marker 
D+ = biopsy confirmed bladder cancer 
D- = no disease indicated 
 
Sensitivity = Prob( M+ | D+) 
Specificity = Prob(M− | D− ) 
 
When evaluating the properties of both markers together, sensitivity will be the 
probability that either of the urine markers is positive given that a patient has a 
positive biopsy, and specificity will be the probability that both of the markers are 
negative given that the patient is without recurrence.  In order to test the 
differences between the area underneath the curves (AUCs) for the single marker 
versus combined marker approach, we will compute the U-statistic of DeLong et. 
al.  (30) 
 
b. 
A second type of analysis will be the anticipatory estimate of sensitivity and 
specificity of each of the urine markers and the combination.  It has been 
hypothesized that the BTA Stat or NMP-22 Bladder Chek may be able to detect 
the presence of cancer earlier than cystoscopy.  If this is true, then we’d expect a 
fair number of false positives since the clinical diagnosis might not follow for 
several months.  To evaluate whether this hypothesis is true, an analysis will be 
performed on the time course of the follow-up BTA Stat and NMP-22 tests and 
cystoscopy.  In this case, sensitivity and specificity will not be based on 
concurrent disease status but instead disease status at a future time t.  The 
anticipatory period can be varied to assess the lead-time provided by each of the 
tests. 
 
11.4    Data and Safety Monitoring Committee Oversight 
 
a. 
Regular study monitoring (described in more detail below) includes an 
assessment of accrual, adverse events and study outcome.  In particular, the 
SWOG Data and Safety Monitoring Committee monitors accrual, and studies with 
accrual concerns are targeted for discussion at the bi-annual meetings.  In 
addition, NCI guidelines for study monitoring will be followed, recognizing that it 
often takes approximately 6 months for regulatory approvals at the institutions 
before an accrual rate can accurately be assessed.  During quarters 5 and 6, if 
the accrual is less than 20% of projected, the study will be considered infeasible, 
and closure will be recommended to the Data and Safety Monitoring Committee.  
If accrual is between 20% and 50% of projected, then attempts will be made to 
improve accrual in the next six month period.  By quarter 8 (at the latest), if 
accrual is below 50% of projected, the trial will be assessed for an amendment to 
reflect actual accrual, with implications on study relevance and feasibility to be 
discussed with the Data and Safety Monitoring Committee, the study committee, 
and the National Cancer Institute. 
 

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S0337 
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b. 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  
The Committee consists of the four members from outside of the Southwest 
Oncology Group, three Southwest Oncology Group members, three non-voting 
representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential 
reports every 6 months from the Southwest Oncology Group Statistical Center, 
and will meet at the Group's bi-annual meetings as necessary.  The Committee 
will be responsible for decisions regarding possible termination and/or early 
reporting of the study. 
 
 
12.0 
DISCIPLINE REVIEW 
 
There will be no formal discipline review 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 28 working days 
prior to planned start of treatment). 
 
13.2 
Phone or Web Registration 
 
For either phone or web registration, the individual registering the patient must have 
completed the appropriate Southwest Oncology Group Registration Form. The completed 
form must be referred to during the registration but should not be submitted as part of the 
patient data. 
 
The individual registering the patient must also be prepared to provide the treating 
institution's name and ID number in order to ensure that the current (within 365 days) date 
of institutional review board approval for this study has been entered into the data base.  
Patients will not be registered if the IRB approval date has not been provided or is > 365 
days prior to the date of registration. 
 
13.3 
Registration procedures 
 
a. 
You may register patients from Member, CCOP, UCOP and approved Affiliate 
institutions to a therapeutics study using the SWOG Registration program. To 
access the Registration program go to the SWOG Web site (http://swog.org) 
and click on the Logon link to go to the SWOG Members Area logon page 
(https://swog.org/visitors/logon.asp).  This Web program is available at any time 
except for periods listed under Down Times.  Log on as an Individual User 
using your SWOG Roster ID Number and individual web user password.  Help 
for the logon process may be found at https://swog.org/visitors/logonhelp.asp. 
After you have logged on, click on the Clinical Trials link and then the Patient 
Reg link to go to the Entry Page for the Patient Registration program. If you are 
a Registrar at an institution with Internet access you are encouraged to register 
this way.  For new users, the link to a "Starter Kit" of help files may be found by 
clicking on Starter Kit link at the logon page. 
 
 

Revised 6/19/12  
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To register a patient the following must be done (in order): 
 
1. 
You are entered into the Southwest Oncology Group Roster and issued a 
SWOG Roster ID Number,  
 
2. 
You are associated as an investigator or CRA/RN to the institution where 
a registration is occurring, and  
 
3. 
You are granted permission to use the Patient Registration program at 
that institution.  
 
For assistance with points 1 and 2 call the SWOG Operations Office at 210/614-
8808. For point 3 you must contact your Web User Administrator.  Each SWOG 
institution has one or more Web User Administrators who may set up Web Users 
at their institution and assign permissions and passwords to these users. For 
other password problems or problems with the Patient Registration program, 
please e-mail webreghelp@crab.org. Include your name, Roster ID Number, and 
telephone number, when the problem occurred, and exactly what you were doing. 
 
b. 
If the Web Reg program is not used, the registration must be done by phone. 
 
Member, Affiliate, CCOP, and UCOP Institutions 
 
Registration by phone of patients from Member, Affiliate, CCOP, and UCOP 
institutions must be done through the Southwest Oncology Group Data 
Operations Center in Seattle by telephoning 206/652-2267, 6:30 a.m. to 4:00 p.m. 
Pacific Time, Monday through Friday, excluding holidays. 
 
 
13.4 
For either method of registration, exceptions to Southwest Oncology Group registration 
policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirements 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 

 
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14.3 
Data Submission Procedures 
 
a. 
Southwest Oncology Group institutions must submit data electronically via the 
Web by using the SWOG CRA Workbench.  To access the CRA Workbench, go 
to the SWOG Web site (http://swog.org) and logon to the Members Area.  After 
you have logged on, click on the CRA Workbench link to access the home page 
for CRA Workbench website.  Next, click on the Data Submission link and follow 
the instructions.  For new users, the link to a "Starter Kit" of help files may be 
found by clicking on the Starter Kit link at the Members’ logon page. 
 
To submit data via the web the following must be done (in order): 
 
1.  
You are entered into the Southwest Oncology Group Roster and issued a 
SWOG Roster ID Number, 
2.  
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, and 
3.  
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to submit data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.   
 
b. 
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 
submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do not 
use cover sheet for faxed data. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 28 DAYS OF REGISTRATION:   
 
Submit copies of the following: 
 
S0337 Prestudy  
 
Pathology Reports 
 
S0337 Treatment Summary Form  
 
S0337 Adverse Event Summary Form  
 
S0337 Cystoscopy and Urine Markers Form  
 
Submit materials outlined in Section 15.0 to the SWOG Repository in Colorado. 
 
b. 
AT MONTH 3 CYSTOCOPY: 
 
Submit materials outlined in Section 15.2 to Lab #135. 
 
 

 
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c. 
EVERY 3 MONTHS FOR 2 YEARS AND THEN EVERY SIX MONTHS UNTIL 4 
YEARS AFTER REGISTRATION: 
 
Submit a copy of the S0337 Disease Assessment and Follow-Up Form and 
S0337 Cystoscopy and Urine Markers Form. 
 
d. 
WITHIN 14 DAYS OF RECURRENCE OR PROGRESSION TO MUSCLE 
INVASIVE DISEASE: 
 
Submit a copy of the S0337 Disease Assessment and Follow-Up Form and 
pathology report.  For those agreeing to banking, submit tissue per Section 15.0 
at first recurrence. 
 
e. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH:  
 
Submit copy of the Notice of Death. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Tissue Specimens for Banking for Future Studies of As Yet To Be Determined Molecular 
Markers 
 
a. 
With patient’s consent, a representative bladder tumor tissue paraffin-embedded 
block must be submitted at the following times (see Section 9.0):  prestudy from 
the TURBT for the index tumor and at first recurrence. 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage:   
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp),  
or via the link on the S0337 protocol abstract page on the SWOG website 
(www.swog.org). 
 
c. 
Specimen collection kits are not being provided for the tissue submission; sites 
will use institutional supplies. 
 
15.2 
Whole Blood Specimens for Banking for Genotyping 
 
a. 
With patient’s consent, whole blood specimens must be submitted at the 
timepoints listed below.  Collection instructions are outlined in Section 15.2c and 
submission instructions are outlined in Section 15.2e. 
 
b. 
With patient’s consent, whole blood specimens must be submitted at the 
following times (see Section 9.0):  at Month 3 cystoscopy. 
 
c. 
On the day of the 3 month cystoscopy, draw the blood sample into the Paxgene 
blood tube (8.5 mL).  Invert 5 times to mix.  Place upright in a sealed plastic bag 
in a 4°C refrigerator.  On the next Monday, Tuesday, or Wednesday, ship the 
specimen to Dr. Reeder’s laboratory (Lab #135) in the infectious substance 
container with the provided shipping label following the Federal guidelines for 
shipment described above.  Blood should be shipped on ice packs by overnight 
carrier Monday through Wednesday only. 
 

 
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Revised 6/19/12 
 
 
d. 
Specimen collection kits may be ordered as follows:  After patient is registered 
and the Month 3 visit is scheduled, contact Dr. Jay Reeder’s laboratory at the 
University of Rochester (585/275-1191) to obtain Paxgene blood tube for the 
blood draw at the Month 3 visit.  The Paxgene blood tube will be shipped to you in 
an infectious substance shipping container which is to be used to ship the 
specimen to Dr. Reeder’s laboratory. 
 
e. 
SHIPPING SAMPLES 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked 
using the SWOG online Specimen Tracking system. SWOG members 
may log on the online system via the CRA Workbench. To access the 
CRA Workbench, go to the SWOG Web site (http://swog.org) and logon 
to the Members Area. After you have logged on using your SWOG roster 
ID number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. First time non- SWOG users 
must 
refer 
to 
start-up 
instructions 
located 
at 
https://gill:crab.org/SpecTrack/. 
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The 
Specimen Submission Form is NOT required when the online system is 
used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact 
the Data Operations Center at 206/667-2267 to be routed to the Data 
Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate Southwest 
Oncology Group laboratory for submission of bone marrow, serum, and 
peripheral blood samples for Southwest Oncology Group Repository 
Submission and SNP testing is identified as follows: 
 
Lab #135:  
Dr. Reeder’s Laboratory 
Phone: 585/275-1191 
Contact:  Sue Schoen 
 
2. 
Federal guidelines for the shipment of blood products: 
 
a. 
The tube must be wrapped in an absorbent material. 
 
b. 
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
 

 
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c. 
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 
d. 
Pack the Styrofoam shipping container in a cardboard box. 
 
e. 
Mark the box "Biohazard". 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability 
 
For each drug supplied for a study, an accountability ledger containing current and accurate 
inventory records covering receipt, dispensing, and the return of study drug supplies must be 
maintained.  Drug supplies must be kept in a secure, limited access storage area under the 
recommended storage conditions.  During the course of the study, the following information must 
be noted on the accountability ledger; the identification code of the subject to whom drug is 
dispensed, the date(s) and quantity of drug dispensed to the subject, and the date(s) and quantity 
of drug returned by the subject; subjects should return empty containers to the investigator, with 
the return noted on the ledger.  These Accountability Forms must be readily available for 
inspection and are open to FDA or NCI inspection at any time. 
 
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. 
 
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.  
 

 
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(Directions for routine reporting are provided in Section 14.0.) Additionally, certain 
adverse events must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. The following guidelines prescribe 
expedited adverse event reporting for this protocol. Also see Appendix 18.1 for 
general and background information about expedited reporting. 
 
b. 
Reporting method 
 
This study requires that expedited adverse event reporting use the NCI’s 
Adverse Event Expedited Reporting System (AdEERS).  The NCI’s guidelines for 
AdEERS can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adeers.htm 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via 
AdEERS. When Internet connectivity is disrupted, a 24-hour notification is to be 
made to the SWOG Operations Office by telephone at 210-614-8808 or by email 
at adr@swog.org.  Once Internet connectivity is restored, a 24-hour notification 
that was made by phone or using adr@swog.org must be entered electronically 
into AdEERS by the original submitter at the site. 
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1.  
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agent used in this study is gemcitabine. If there is 
any question about the reportability of an adverse event or if on-line AdEERS 
cannot be used, please telephone or email the SAE Specialist at the Operations 
Office, 210/614-8808 or adr@swog.org, before preparing the report. 
 
 

 
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Table 16.1: 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a Non-CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent Gemcitabine. 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
AdEERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Section 16.1f. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
 
 
May 5, 2011 
 

 
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f. 
Additional Instructions or Exceptions to AdEERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent 
under a non-CTEP-IND: 
 
1. 
Group-specific instructions 
 
Supporting Documentation Submission - Within 5 calendar days 
submit the following to the SWOG Operations Office by fax to 210-
614-0006 or mail to the address below: 
• 
Printed copy of the first page of the AdEERS report 
• 
Copies of clinical source documentation of the event 
• 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center, copies of Off Treatment 
Notice and/or Notice of Death. 
 
2. 
For this study, the adverse event listed below does not require 
expedited reporting via AdEERS: 
• 
Grade 4 myelosuppression. 
 
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
 A secondary malignancy is a cancer caused by treatment for a 
previous 
malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
 
SWOG requires all secondary malignancies that occur following 
treatment with an agent under a Non-NCI IND to be reported via 
AdEERS.  Three options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/default.htm#adverse_eve
nts_adeers 
 
2. 
Supporting documentation should be submitted to CTEP in 
accordance with instructions provided by the AdEERS system.    A 
copy of the report and the following supporting documentation must 
also be submitted to SWOG Operations Office within 30 days: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
 

 
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SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 

 
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17.0 
BIBLIOGRAPHY 
 
1. 
Bouffioux C, et al.  Intravesical adjuvant chemotherapy for superficial transitional cell bladder 
carcinoma:  results of 2 European Organization for Research and Treatment of Cancer 
randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations 
and short-term versus long-term treatment.  J Urol 153:934-941, 1995. 
 
2. 
Burnand KG, et al.  Single dose intravesical thiotepa as an adjuvant to cystodiathermy in the 
treatment of transitional cell bladder carcinoma.  Br J Urol 48:55-59, 1976. 
 
3. 
Oosterlinck W, et al.  A prospective European Organization for Research and Treatment of 
Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a 
single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of 
the bladder.  J Urol 149:749-752, 1993. 
 
4. 
Shuin T, et al.  A phase II study of prophylactic intravesical chemotherapy with 4-epirubicin in 
recurrent superficial bladder cancer:  comparison of 4-epirubicin and adriamycin.  Cancer 
Chemother Pharmacol 35:52-56, 1994. 
 
5. 
Solsona E, et al.  Effectiveness of a single immediate mitomycin C instillation in patients with low 
risk superficial bladder cancer:  short and long-term follow-up.  J Urol 161:1120-1123, 1999. 
 
6. 
Jemal A, et al.  Cancer statistics, 2003.  CA Cancer J Clin 53:5-26, 2003. 
 
7. 
Messing EM, et al.  Comparison of bladder cancer outcome in men undergoing hematuria home 
screening versus those with standard clinical presentations. Urology 45:387-397, 1995. 
 
8. 
Borhan A, et al.  Grade progression and regression in recurrent urothelial cancer. J Urol 
169:2106-2109, 2003. 
 
9. 
Cina SJ, et al.  Correlation of cystoscopic impression with histologic diagnosis of biopsy 
specimens of the bladder. Hum Pathol 32:630-637, 2001. 
 
10. 
Klan R, Loy V, Huland H.  Residual tumor discovered in routine second transurethral resection in 
patients with stage T1 transitional cell carcinoma of the bladder. J Urol 146:316-318, 1991. 
 
11. 
Kiemeney L., et al.  Should random urothelial biopsies be taken from patients with primary 
superficial bladder cancer? A decision analysis. Members of the Dutch South-East Co-Operative 
Urological Group. Br J Urol 73:164-171, 1994. 
 
12. 
See WA, Rohlf DP, Crist SA.  In vitro particulate adherence to fibronectin: correlation with in vivo 
particulate adherence to sites of bladder injury. J Urol 147:1416-1423, 1992. 
 
13. 
Hyacinthe LM, et al.  Inhibition of bladder tumor cell implantation in cauterized urothelium, without 
inhibition of healing, by a fibronectin-related peptide (GRGDS). Ann Surg Oncol 2:450-456, 1995. 
 
14. 
Duque JL, Loughlin KR.  An overview of the treatment of superficial bladder cancer: Intravesical 
chemotherapy. Urol Clin North Am 27:125-135, 2000. 
 
15. 
Dalbagni G, Herr HW.  Current use and questions concerning intravesical bladder cancer group 
for superficial bladder cancer. Urol Clin North Am 27:137-146, 2000. 
 
16. 
Zincke H, et al.  Influence of thiotepa and doxorubicin instillation at time of transurethral surgical 
treatment of bladder cancer on tumor recurrence: a prospective, randomized, double-blind, 
controlled trial. J Urol 129:505-509, 1983. 
 
17. 
Stadler WM.  Gemcitabine doublets in advanced urothelial cancer. Semin Oncol 29:15-19, 2002. 
 

 
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18. 
von der Maase H.  Current and future perspectives in advanced bladder cancer: is there a new 
standard? Semin Oncol 29:3-14, 2002.  
 
19. 
Hussain M, Vaishampayan U, Smith DC.  Novel gemcitabine-containing triplets in the 
management of urothelial cancer. Semin Oncol 29:20-24, 2002. 
 
20. 
von der Maase H, 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 18:3068-3077, 2000. 
 
21. 
Dalbagni G, et al.  Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory 
transitional-cell carcinoma of the bladder. J Clin Oncol 20:3193-3198, 2002. 
 
22. 
O’Donnell M.  Gemzar in superficial bladder cancer: a new therapeutic option?  Presented in 
Workshop of Intravesical Therapy, Rome Italy. September 2002. 
 
23. 
Laufer M, et al.  Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the 
bladder: a phase I and pharmacokinetic study. J Clin Oncol 21:697-703, 2003 
 
24. 
Witjes JA, van de Heijden AG, Vriesema JLJ, Peters GJ, Laan A, Schalken JA. Intravesical 
gemcitabine - a phase I and pharmacokinetic study.  Eur Urology 45:182-186, 2004. 
 
25. 
De Berardinis E, Antonini G, Peters GJ, Loves WJP, van der Born K, Codacci-Pisanelli G, Di 
Silverio F.  Intravesical administration of gemcitabine in superficial bladder cancer: a phase I study 
with pharmacodynamic evaluation. BJU International 93:491-494, 2004. 
 
26. 
Buettner H, Stoffregen C, Heinemann V, Boehle A.  Immediate postoperative instillation of 
gemcitabine into the bladder in patients with superficial bladder cancer.  in:  Proc Am Soc Clin 
Oncol 39th annual meeting program/proceedings; 2003 May 31 - June 3; Chicago. Alexandra (VA: 
American Society of Clinical Oncology. Abstract 1785. 
 
27. 
Maddineni S, Sangar V, King H, Betts C, O'Flynn K, Lupton E, George N, Ramani V.  A phase I 
dose escalation and pharmacokinetic trial of intravesical gemcitabine in the treatment of recurrent 
superficial transitional cell carcinoma of the bladder.  In European Association of Urology Meeting; 
2003, March 12-15; Madrid.  Abstract. 
 
28. 
Palou J, Segarra J, Oliver A, Villavicencio H, Salvador J, Frias J, Duque B, Carcas A, Garcia-
Ribas I.  A Phase I pharmacokinetic study of a single intravesical instillation of gemcitabine 
administered immediately after transurethral resection plus multiple random biopsies in patients 
with superficial bladder cancer. J Urol 172:485-488, 2004. 
 
29. 
Pocock SJ, Simon R.  Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial.  Biometrics 31(1):103-115, 1975. 
 
30. 
DeLong ER, DeLong CM, Clarke-Pearson DL.  Comparing the areas under two or more 
correlated receiver operating characteristic curves:  a nonparametric approach.  Biometrics 
44:837-45, 1988. 
 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
18.2 
Emergency Unblinding Guidelines 
 
18.3 
Correlative Studies for S0337 
 
 
 

 
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18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. (Directions for routine reporting are provided in 
Section 14.0.) Additionally, certain adverse events must be reported in an expedited 
manner to allow for more timely monitoring of patient safety and care. Expedited adverse 
event reporting principles and general guidelines follow; specific guidelines for expedited 
adverse event reporting on this protocol are found in Section 16.1. 
 
All serious adverse events determined to be reportable to the Institutional Review Board 
responsible for the oversight of the patient must be reported according to local policy and 
procedures.  Documentation of this reporting should be maintained for possible inspection 
during quality assurance audits. 
 
Steps to determine if an adverse event is to be reported in an expedited manner 
(This includes all events that occur while on treatment or within 30 days of the last dose of 
protocol treatment.) 
 
Step 1: Determine whether the patient has received an investigational agent, commercial 
agent, or a combination of investigational and commercial agents. 
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
When a study includes both investigational and commercial agents, the following rules 
apply.   
• 
Concurrent administration: When an investigational agent(s) is used in 
combination with a commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration:   When a study includes an investigational agent(s) 
and a commercial agent(s) on the same study arm with sequential administration 
all expedited reporting of adverse events should follow the guidelines for the type 
of agent being given.  For example, if the patient begins the study on the 
investigational agent(s), then all expedited reporting of adverse events should 
follow guidelines for the investigational agent(s).  Once the patient begins 
receiving the commercial agent(s) then all expedited reporting of adverse events 
should follow the guidelines for commercial agent(s).   
 
Step 2: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE that provides help for classifying and locating terms.  
 
 
 
 

 
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Step 3:  Grade the event using the NCI CTCAE version specified in the protocol for 
reporting serious adverse events. 
 
Step 4: Determine if the adverse event is Expected or an Exception to Expedited 
Reporting.  Expected events are those that have been previously identified as resulting 
from administration of the agent and are listed in one of the following:   
 
• 
The current NCI SPEER (Specific Protocol Exceptions to Expedited Reporting) 
for treatments using agents provided under an NCI-held IND, or an equivalent 
listing for treatments using agents provided under a Non-CTEP-held IND; located 
in Section 3.0 of the protocol. 
• 
For treatments using commercial agents, the current CAEPR (Comprehensive 
Adverse Event and Potential Risks), ASAEL (Agent Specific Adverse Event List), 
or other list of expected toxicities located in Section 3.0 of the protocol, or the 
drug package insert.   
• 
Exception to Expedited reporting located in Section 16.1f of the protocol. 
 
An adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in one of the areas 
outlined above. 
 
Step 5:  Determine whether the adverse event involved hospitalization or a prolongation 
of hospitalization (≥ 24 hours). 
 
Step 6:  Additionally, for commercial drugs, determine whether the adverse event is 
related to the protocol therapy. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite.  Consult the appropriate table for expedited reporting 
criteria for commercial agent(s). 
 
NOTE:   Any event that occurs more than 30 days after the last dose of study agent and 
is attributed (possible, probable, or definite) to the study agent(s) must be reported 
according to the instructions above and as outlined in the appropriate table in Section 
16.1. 
 
 

 
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18.2 
Emergency Unblinding Guidelines 
 
a. 
General Considerations 
 
The randomized regimen for this study includes a blinded drug, which is either 
gemcitabine or placebo.  During the course of this study it may become 
necessary to identify (or unblind) a patient's treatment assignment.  The 
circumstances that will warrant unblinding and the procedure for unblinding are 
described in this Appendix. 
 
b. 
Criteria for Emergency Unblinding 
 
In general, treatment assignments will not be unblinded unless there is a 
compelling medical or ethical reason that the treatment should be identified.  In 
most circumstances it will be appropriate to treat the patient or person who 
received blinded drug as though he or she received gemcitabine, irrespective of 
the drug actually received.  Therefore, unblinding should seldom be necessary. 
 
The following events MAY require unblinding of treatment assignments in this 
study: 
 
1. 
A compelling medical need as determined by a physician, e.g., existence 
of a condition for which knowledge of the patient's treatment assignment 
is necessary for the selection of appropriate care. 
 
2. 
Administration of blinded drug to a person other than the patient. 
 
c. 
Procedure for Emergency Unblinding 
 
Emergency unblinding of treatment assignments for patients on this study will be 
performed by the Washington Poison Center (WPC), upon approval from a 
designated physician (either one of the WPC's resource physicians or Dr. Edward 
Messing).  The procedure for emergency unblinding the treatment assignment for 
a patient on this study is as follows: 
 
1. 
All requests for emergency unblinding must be made by the registering 
physician or his/her designee. 
 
2. 
Call the WPC collect at 206/526-2121 from outside Washington State or 
toll free at 800/222-1222 from within Washington State.  The WPC is 
accessible 24 hours per day, 365 days per year. 
 
3. 
The person calling the WPC must be prepared to provide the following 
information: 
 
Study number (S0337) 
 
SWOG Patient Number (e.g., "999999") 
 
Patient Initials 
 
Name and telephone number of the caller 
 
Reason emergency unblinding is thought to be required 
 
 
 

 
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4. 
The WPC will contact one of its resource physicians and provide the 
information received from the caller.  If none of the WPC's resource 
physicians can be contacted, then the WPC will contact Dr. Edward 
Messing.  The contacted physicians will evaluate the need for emergency 
unblinding and provide the WPC either approval to unblind or a 
recommendation for treatment, if any, while maintaining blinding.  The 
WPC will then call the person who initiated the unblinding request and tell 
him/her either the treatment assignment or the resource physician's 
treatment recommendation. 
 
5. 
If the WPC is unable to contact any of its resource physicians or Dr. 
Messing within three hours after receiving the request for emergency 
unblinding, then the WPC will notify the person who initiated the 
unblinding request that treatment assignment will not be unblinded at that 
time and treatment of the patient or person who received blinded drug 
should proceed as if the blinded drug is gemcitabine.  In such cases, the 
WPC will continue to attempt to contact the resource physicians, and 
when one of them is contacted, will proceed as in #4 above. 
 
6. 
Any patient whose treatment assignment is emergency unblinded will 
receive no further blinded drug, but should continue all other protocol 
treatment if his/her medical condition permits. 
 
7. 
Unblinding of treatment assignments for any reason must be 
documented on the S0337 Treatment Summary Form. 
 
Questions regarding the unblinding may be directed to any of the 
following resource physicians: 
 
Edward M. Messing, M.D. 
University of Rochester 
Strong Memorial Hospital 
601 Elmwood Avenue, Box 656 
Rochester, NY  14642-0001 
Phone:  585/275-3345 
 
Bruce G. Redman, D.O. 
Southwest Oncology Group  
24 Frank Lloyd Wright Drive 
P.O. Box 483 
Ann Arbor, MI  48106 
Phone:  734/998-7154 
 
Washington Poison Center 
Phone:  206/526-2121 
 

 
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18.3 
Correlative Studies for S0337 
 
Urinary Markers 
 
Hypothesis 
 
The sensitivity of no single test will be as good as that of cystoscopy and cytology to 
detect recurrences of these tumors during monitoring.  However, a combination of non or 
minimally invasive markers will be as sensitive as cystoscopy. 
 
Rationale 
 
The point-of-service bladder cancer marker tests, BTA Stat and NMP-22 Bladder Chek 
have been approved by the FDA as aids to cystoscopy in the diagnosis of bladder cancer.  
Depending on the populations studied, each test has been reported to have sensitivities 
of 35-80% in the detection of bladder cancer, and specificities of 65-90%.  (1-3) However, 
combined performance is not known and the performance of each of the two tests in a 
large population of patients with low risk bladder cancer has only been partially defined.  
In the current study, each test will be performed prestudy and then every three months 
with each surveillance cystoscopy for 2 years (or until recurrence).  This information is 
needed to determine the relative safety with which one or both tests could replace some 
surveillance cystoscopies in this population.  Additionally, based on the pattern of 
recurrences in the placebo arm in S0337, and from other studies, the optimal way for 
using these markers in monitoring superficial bladder cancer can be modeled.  (4)  For 
instance, if the initial recurrence is most likely to happen at the first or second surveillance 
cystoscopy, these tests might be best suited for use after those examinations. 
 
Methods 
 
BTA Stat and NMP-22 Bladder Chek will each be performed prior to the TURBT of the 
index tumor and with each surveillance cystoscopy for 2 years, or until first histologically 
confirmed recurrence (whichever is sooner).  Each test will be performed as per 
manufacturer’s instructions by the research nurse with each institution’s investigators and 
results will be reported to the Southwest Oncology Group Data Operations Office on the 
S0337 Urine Markers Form. 
 
Interpretation of Data 
 
Statistical considerations appear in Section 11.0.  With this information, the ability of each 
test (or combination of tests) to replace any surveillance cystoscopy during the 2 years 
following TURBT will be ascertained.  Performance characteristics of the tests will be 
determined.  Sensitivities, specificities, positive and negative predictive values, and 
accuracy of each test and the combination (either test positive = a positive test) will be 
calculated.  Additionally, the anticipation rate of each marker, independently and 
combined, in this longitudinal study (i.e. what proportion of “false positive” results predict 
future tumor appearance and how long after the first positive test result tumors become 
cystoscopically apparent), and how consistently that marker remains positive before 
cancer is diagnosed, will be determined. 
 
Additionally, how best to use each or both tests instead of cystoscopy, will be compared 
with published recommendations (e.g.  alternating one marker with cystoscopy) in terms 
of benefit and cost effectiveness.  (5) 
 
 

 
 
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References: 
 
1. 
Sarosdy et al. Urology 50:349, 1997. 
 
2. 
Pode et al.  J Urol 161:443, 1999. 
 
3. 
Grossman et al.  JAMA 293:810, 2005. 
 
4. 
Messing et al, J Urol 173:249a, 2005. 
 
5. 
Lotan Y, Roehborn, CG.  J Urol 167:75-79, 2002. 
 
 
 

 
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Informed Consent Model for S0337 
 
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:  
 
This model informed consent form has been reviewed by the DCT/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 Southwest Oncology Group 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 
Southwest Oncology Group Operations Office. 
 
Readability Statistics:   
 
Flesch Reading Ease  
61.6 (targeted above 55) 
Flesch-Kincaid Grade Level 8.8 (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 the Southwest Oncology Group. 
 
The "Southwest Oncology Group" 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 the Southwest Oncology Group.  This includes consent forms for studies where 
all patients are registered directly through the Southwest Oncology Group Data Operations 
Office, all intergroup studies for which the registration is being credited to the Southwest 
Oncology Group (whether the registration is through the SWOG Data Operations Office or  
 

 
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directly through the other group), as well as consent forms for studies where patients are 
registered via CTSU and the registration is credited to the Southwest Oncology Group. 
• 
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: "If You Have Cancer…What You Should Know 
about Clinical Trials".  This pamphlet may be ordered on the NCI Web site at 
http://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.  
 
 

 
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S0337, "A Phase III Blinded Study Of Immediate Post-TURBT 
Instillation Of Gemcitabine Versus Saline In Patients With Newly 
Diagnosed Or Occasionally Recurring Grade I/II Superficial 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. 
 
You are being asked to take part in this study because you have newly diagnosed superficial 
bladder cancer or superficial bladder cancer that has come back.  
 
Who is doing this study? 
 
The Southwest Oncology Group (SWOG) is sponsoring this trial.  SWOG is an adult cancer 
clinical trials organization. SWOG is funded through the National Cancer Institute, and its 
network consists of almost four thousand physicians at almost three hundred institutions 
throughout the United States.  Your study doctor has met all requirements to be a member of 
SWOG and to perform National Cancer Institute-funded research through this Group. 
 
Why is this study being done? 
 
The type of bladder tumor that you have has a relatively high chance of coming back in 
your bladder after it has been removed.  It usually comes back in a different spot of your 
bladder than where it was originally. 
 
The purpose of this study is to determine if gemcitabine, a chemotherapy drug that is 
effective against very advanced bladder cancer when given through a vein (intravenously) 
is also effective against earlier stage bladder cancers when given into your bladder 
(intravesically).  Specifically, the study will determine whether gemcitabine is more likely 
than saline (salt water) to lower the chances of your tumor recurring if given into the 
bladder within 3 hours after your tumor is removed. 
 
In this study, the drug gemcitabine is being used in a new (investigational) way. 
 
Since the final pathology will not be available until after you receive treatment, there is a 
possibility that you may not have cancer, but still may undergo treatment.  The likelihood 
of this is extremely small in view of known data that indicates that experienced urologists 
are capable of accurately assessing the presence of tumor. 
 
 

 
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How many people will take part in the study? 
 
About 340 people will take part in this study. 
 
What will happen if I take part in this research study?   
 
Before you begin the study …  
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
• Your doctor will review your medical history and perform a physical examination. 
• Your doctor will perform a cystoscopy (looking into the bladder with a flexible or rigid 
endoscope, usually in the clinic under local anesthesia) to look inside your bladder, with the 
collection of urine for cytology (a laboratory evaluation for cancer cells in the urine). 
• An x-ray of your kidneys (intravenous pyelogram or CAT scan) will be performed if you 
have not had that done within the last six months.  
• Your urine will be collected for urinalysis and urine culture.  If you have a urinary tract 
infection you cannot participate on this study.  Tell your doctor if you believe you have 
developed a urinary tract infection since the urine culture was collected. 
• Routine blood tests will be performed to evaluate your white cells, red cells and platelets, and 
the function of your liver and kidneys. 
 
During the study: 
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures. 
 
You will be "randomized" into one of the study groups described below.  Randomization means 
that you are put into a group by chance.   Neither you nor your doctor will either know or choose 
the group you will be in.  You will have an equal chance of being placed in either group. 
 
• After  you agree to take part in the study but before you receive treatment, your urine will be 
collected for research studies.  The tests performed will be the NMP-22 Bladder Chek and 
BTA Stat test.  Part of this study is to see whether these tests can predict recurrence as well as 
cystoscopy alone.  Your urine will be collected once every three months for the first two 
years for these tests. 
• The study involves one intravesical instillation treatment of either gemcitabine or saline (salt 
water) into the bladder immediately following the TURBT (trans-urethral resection of 
bladder tumor) procedure.  Saline (salt water) is a placebo, not a form of treatment for 
superficial bladder cancer.  It does not contain any medication.  You will have a catheter tube 
inserted in your bladder through the urethra.  About ¼ cup of liquid containing either the 
study drug (gemcitabine 2,000 mg in 100 mL of saline) or saline alone (100 mL) will be 
instilled into your bladder after all the urine has been drained out.  You will be asked to hold  
 
 

 
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the liquid in your bladder for about 1 hour.   After about 1 hour the liquid will be drained 
from the bladder through the catheter.  If you experience discomfort while the liquid is in 
your bladder, you should notify your urologist who may choose to drain your bladder earlier 
than the 1 hour dwell time.  Similarly, if you wish the liquid to be drained earlier than 
planned, notify your urologist and the infusion will be stopped and the bladder drained.  
Additionally, if immediately after your surgery your urine is found to be quite bloody, your 
urologist may choose to irrigate your bladder with liquid.  If the urine becomes clear within 3 
hours, the liquid could still be instilled at the time. 
• If your urologic surgeon believes for any number of reasons, including that there is too much 
post-operative bleeding, or that removal of the tumor went so deep into the bladder wall that 
instilling the liquid might be dangerous, he/she will not place the liquid into your bladder. 
• You will be asked to keep track of any side effects you have during the treatment, and will be 
asked about them by your doctor or the study nurse.   
• Between 7 and 14 days after you receive the intravesical treatment, routine blood tests will be 
performed to evaluate your white cells and platelets and to test your liver function. 
• Every 3 months for the first two years, then every 6 months for the next two years, your 
doctor will review your medical history and perform a physical examination. 
• Every 3 months for the first two years, then every 6 months for the next two years, your 
doctor will perform a cystoscopy (looking into the bladder with a flexible or rigid endoscope, 
usually in the clinic under local anesthesia) to look inside your bladder, with the collection of 
urine for cytology (a laboratory evaluation for cancer cells in the urine).  At each evaluation, 
if either test is abnormal your doctor will arrange for you to have a bladder biopsy performed.  
If the cancer comes back, your doctor will discuss with you other options for treatment of 
your cancer at that point. We will continue to follow you to see how you are doing for up to 4 
years after you start the study. 
 
How long will I be in the study? 
You will continue as detailed above for up to 4 years from the start of the study.  You will need 
routine follow-up evaluations (cystoscopy and urinary cytology) every 3 months the first and 
second year and every 6 months for the next two years.  
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
intravesical gemcitabine/saline can be evaluated by your doctor.  Another reason to tell your 
doctor that you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you. 
 
The study doctor may end your participation in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
 

 
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What side effects or risks can I expect from being in the study?  
 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects that 
may happen.  Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects. Many side effects go away soon after the 
gemcitabine/saline instillation.  In some cases, side effects can be serious, long lasting, or 
may never go away.   
 
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
 
Risks and side effects related to the bladder tumor resection (TURBT) and intravesical 
gemcitabine include:  
 
Likely 
• 
Bladder irritation causing urinary frequency or burning 
• 
Hematuria (blood in the urine) 
• 
Bladder spasms 
 
Less Likely 
 
• 
Bladder perforation (a hole in your bladder).  This usually will require you 
to have a draining catheter for several days longer than normal after your 
surgery, and rarely might require you to undergo an operation to repair 
your bladder. 
• 
If gemcitabine is put into your bladder, there might be other risks 
including the risk of the drug getting into your blood stream.  If this 
happens, you may also experience low white blood cell or platelet counts, 
which could cause increased susceptibility to infection or bleeding.  Very 
rarely anemia (low red blood cell count) causing fatigue and sometimes 
requiring transfusions may occur. 
 
Rare but Serious 
 
In a few patients who received gemcitabine through a vein, the following rare, but serious 
side effects were seen: 
 
• 
Fluid in your lungs, which could make you short of breath, wheeze or 
cough 
• 
Kidney stress or damage as shown by abnormal kidney function tests.  You 
may notice blood and/or protein in your urine. 
 
 
 

 
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Risks and side effects related to the bladder tumor resection (TURBT) and intravesical 
saline include:  
 
Likely 
• 
Bladder irritation causing urinary frequency or burning 
• 
Hematuria (blood in the urine) 
• 
Bladder spasms 
 
Less Likely 
 
• 
Bladder perforation (a hole in your bladder).  This usually will require 
you to have a draining catheter for several days longer than normal after 
your surgery, and rarely might require you to undergo an operation to 
repair your bladder. 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a 
baby while on this study.  It is important you understand that you need to use birth control 
while on this study.  Check with your study doctor about what kind of birth control 
methods to use and how long to use them.  Some methods might not be approved for use in 
this study. 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better.  While doctors hope 
intravesical gemcitabine will be more useful against cancer compared to the usual 
treatment, there is no proof of this yet. We do know that the information from this study 
will help doctors learn more about intravesical gemcitabine as a treatment for cancer.  This 
information could help future cancer patients. 
 
 
What other choices do I have if I do not take part in this study? 
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study.  This may 
include other intravesical treatments, surgery to remove the bladder, radiation 
therapy to the bladder, or systemic chemotherapy, 
• Taking part in another study, 
• Getting no treatment. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 

 
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Will my medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
• The Southwest Oncology Group  
• Lilly Pharmaceuticals  
 
What are the costs of taking part in this study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  Because instillation of chemotherapy immediately after surgery 
is frequently done for bladder cancer, you and/or your insurance company may need to pay for 
this as well.  If there are complications of the surgery or the drug instillation, you or your health 
insurance may be required to pay for the expenses created by caring for/or correcting these 
complications. 
 
Administration of the drug will be (provided free of charge/charged in the usual way).  The parts 
of the research consisting of keeping research records will be paid by those organizing and 
conducting the research.  The research requires that you receive certain standard medical tests 
and examinations.  These standard tests and examinations will be (charged in the usual 
way/provided at a reduced rate).  (local institutions must choose the option that best fits the 
hospital's situation).  Lilly Pharmaceuticals has agreed to pay (up to a defined amount per test) 
for the NMP-22 Bladder Chek and BTA Stat tests. 
 
Lilly Pharmaceuticals will provide you with the investigational agent gemcitabine or saline at no 
cost to you.   
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .    You 
can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 

 
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What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.   
 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study. We will tell you about important new information 
from this or other studies that may affect your health, welfare, or willingness to stay in this study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
  
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
  
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of 
people who review the research to protect your rights) at __________________ (telephone 
number).  [Note to Local Investigator: Contact information for patient representatives or 
other individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.]    
 
*You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) 
at 888-657-3711 (from the continental US only).   [*Only applies to sites using the CIRB.] 
 
 
 
 

 
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Please note:  This section of the informed consent form is about additional 
research studies that are being done with people who are taking part in the main 
study. You may take part in these additional studies if you want to.  You can still 
be a part of the main study even if you say ‘no’ to taking part in any of these 
additional studies. 
 
You can say "yes" or "no" to each of the following studies.  Please mark your 
choice for each study.   
 
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 
 
Consent Form for Use of Specimens for Research 
About Using Specimens for Research  
Prior to receiving gemcitabine or placebo, you will have a biopsy (TURBT) to remove your 
bladder cancer.  In addition, if your cancer recurs in the future, additional biopsies will be 
performed at that time.  We would like to obtain some of the tissue that was removed both before 
and after the treatment so that we can do some research tests on the tissue.  We would also like to 
collect a sample of your blood 3 months after you receive gemcitabine or placebo.   The goal of 
these research tests it to improve our understanding of your type of bladder cancer and its 
response to the intravesical gemcitabine treatment. 
Your tissue will be kept at: 
Southwest Oncology Group Tumor Tissue Bank: 
University of Colorado HSC at Fitzsimons 
Department of Pathology 
RC-1 South, Room L18-5104 
12801 East 17th Avenue 
Aurora, CO  80010 
Phone:  303/724-3086 
 
We would like to keep some of the tissue and blood that is left over for future research. If you 
agree, these specimens will be kept and may be used in research to learn more about cancer and 
other diseases. Please read the information sheet called "How are Specimens Used for Research" 
to learn more about tissue research.  
The research that may be done with your specimens is not designed specifically to help you. It 
might help people who have cancer and other diseases in the future.  
Reports about research done with your specimens will not be given to you or your doctor. These 
reports will not be put in your health record. The research will not have an effect on your care. 
 
 

 
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Things to Think About  
The choice to let us keep the left over specimens for future research is up to you. No matter what 
you decide to do, it will not affect your care.  
If you decide now that your specimens can be kept for research, you can change your mind at any 
time. Just contact us and let us know that you do not want us to use your specimens. Then any 
specimens that remain will no longer be used for research.  
In the future, people who do research may need to know more about your health. While the 
Southwest Oncology Group may give them reports about your health, it will not give them your 
name, address, phone number, or any other information that will let the researchers know who 
you are.  
Sometimes specimens are used for genetic research (about diseases that are passed on in 
families). Even if your specimens are used for this kind of research, the results will not be put in 
your health records.  
Your specimens will be used only for research and will not be sold. The research done with your 
specimens may help to develop new products in the future.  
Benefits  
The benefits of research using specimens include learning more about what causes cancer and 
other diseases, how to prevent them, and how to treat them.  
Risks  
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
Making Your Choice  
Please read each sentence below and think about your choice. After reading each sentence, circle 
"Yes" or "No."  If you have any questions, please talk to your doctor or nurse, or call our 
research review board at IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
1.  
My specimens may be kept for use in research to learn about, prevent, treat or cure 
cancer.  
Yes 
No 
2.  
My specimens may be kept for use in research about other health problems (for 
example: diabetes, Alzheimer's disease, or heart disease).  
Yes 
No 
3.  
Someone may contact me in the future to ask me to allow other uses of my 
specimens.  
Yes 
No 
 
 
 

 
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If you decide to withdraw your specimens from a Southwest Oncology Group Specimen 
Repository in the future, a written withdrawal of consent should be submitted through 
your treating physician to the Southwest Oncology Group Operations Office.  Please 
designate in the written withdrawal whether you would prefer to have the specimens 
destroyed or returned to the treating physician. 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
 
You will get a copy of this form.    If you want more information about this study, ask your study 
doctor. 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
Participant ________________________________ 
 
Date _____________________________________ 
 
 
 

 
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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 the Southwest Oncology Group.  Your doctor does not work for 
the Southwest Oncology Group, 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 the Southwest Oncology Group and request samples for their studies.  The 
Southwest Oncology Group reviews the way that these studies will be done, and decides if any of the 
samples can be used. The Southwest Oncology Group gets the specimen and information about you from 
your hospital, and sends the specimen samples and some information about you to the researcher.  The 
Southwest Oncology Group 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 the Southwest Oncology Group.  If more 
information is needed, the Southwest Oncology Group 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 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? 
 
The Southwest Oncology Group is in charge of making sure that information about you is kept private.  
The Southwest Oncology Group 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).