Clinical trial NCT00942331
Conditions: Advanced Urothelial Carcinoma Metastatic Bladder Urothelial Carcinoma Metastatic Prostate Carcinoma Metastatic Renal Pelvis Urothelial Carcinoma Metastatic Ureter Urothelial Carcinoma Metastatic Urethral Urothelial Carcinoma Metastatic Urothelial Carcinoma Stage IV Bladder Urothelial Carcinoma AJCC v7 Stage IV Prostate Cancer AJCC v7 Stage IV Renal Pelvis Cancer AJCC v7 Stage IV Ureter Cancer AJCC v7 Stage IV Urethral Cancer AJCC v7 Unresectable Urothelial Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2009-07-15; Completion date: 2021-06-15
Enrollment: 506 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies gemcitabine hydrochloride, cisplatin, and bevacizumab to see how well they work compared with gemcitabine hydrochloride and cisplatin in treating patients with urinary tract cancer that has spread to other places in the body. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with bevacizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether gemcitabine hydrochloride and cisplatin are more effective when given with or without bevacizumab in treating patients with urinary tract cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if patients with advanced transitional cell carcinoma treated with bevacizumab, gemcitabine hydrochloride (gemcitabine) and cisplatin will have increased overall survival when compared to patients treated with gemcitabine, cisplatin, and placebo.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival of these two regimens in patients with advanced transitional cell carcinoma.

II. To compare the proportion of patients who experience an objective response on each regimen.

III. To compare the grade 3 and greater toxicities in patients treated on the two regimens.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, cisplatin IV, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive placebo IV over 30-90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive gemcitabine hydrochloride and cisplatin as in arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab IV over 30-90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 7 years.

Arms: arm 1: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV and placebo IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive placebo IV over 30-90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive gemcitabine hydrochloride and cisplatin as in arm I. Patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab IV over 30-90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Bevacizumab intervention 2: Cisplatin intervention 3: Gemcitabine Hydrochloride intervention 4: Laboratory Biomarker Analysis intervention 5: Placebo Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
Update #12 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
 
PROTOCOL UPDATE TO CALGB 90601 
_________________________________________ 
 
A RANDOMIZED DOUBLE-BLINDED PHASE III STUDY COMPARING GEMCITABINE, 
CISPLATIN, AND BEVACIZUMAB TO GEMCITABINE, CISPLATIN, AND PLACEBO IN 
PATIENTS WITH ADVANCED TRANSITIONAL CELL CARCINOMA 
 
NCI-supplied agent(s): Bevacizumab/Placebo (NSC 704865, IND #113911) 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other :  
 
 
 
 
 Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Please follow 
your IRB of record guidelines. 
 
UPDATES TO PROTOCOL: 
 
Cover Page (page 1): 
-Misty Bova-Solem has replaced Nick Jeffries as Data Coordinator. All contact information has been 
updated. 
-Karla Ballman has replaced Susan Halabi as GU Faculty Statistician. All contact information has been 
updated. 
-Ben Sanford has been removed as Staff Statistician. 
 
Cover Page (page 2): 
-The study document history table has been removed. This table now appears as a separate document on 
the protocol landing page, on the member side of the Alliance website. 
-Data submission for this study will now be performed using Medidata Rave®, and thus the website link 
for Medidata Rave has been added to the left side of the table as an additional resource. 
 
CTSU Contact Information (page 3): 
The CTSU Contact Information table has been updated with the current CTSU boilerplate language. 


2 
 
 
 
Section 5.1 (CTEP Investigator Registration Procedures): 
This section has been retitled “CTEP Registration Procedures” and updated with the current CTSU 
boilerplate language. 
 
Section 5.2 (CTEP Associate Registration Procedures): 
This section has been removed as it is now encompassed within Section 5.1 
 
Section 5.3 (CTSU Registration Procedures): 
This section has been renumbered as Section 5.2 and updated with the current CTSU boilerplate 
language. The remaining sections have been renumbered accordingly. 
 
Section 5.3.3 (Submitting Regulatory Documents): 
-This section has been renumbered as Section 5.2.3.  
-The suite number in the CTSU Regulatory Office mailing address has been changed to 3000. 
 
Section 6.1 (Data Submission): 
-Data submission for this study will now be performed using Medidata Rave®; therefore, all text above 
the table has been replaced with four new paragraphs that outline the new data submission procedures. 
-Reference to submitting forms to the Alliance Statistics and Data Center has been removed from the 
instructions above the table. 
-In the second sentence of the “Common Toxicity Criteria” heading under the data submission table, the 
CTCAE version has been updated from 4.0 to 5.0 for expedited adverse event reporting. The reference to 
the AER section has been updated from 14.0 to 16.0. 
 
Section 9.12 (Hypersensitivity and infusion reactions): 
A sentence has been added to the end of the first paragraph to note that serious adverse events will be 
reported through CTEP-AERS using CTCAE version 5.0. 
 
Section 11.3 (Bevacizumab): 
-The text in the first paragraph under the “Drug Accountability” heading has been replaced with updated 
PMB language regarding drug accountability. 
-In the third paragraph under the “Drug Ordering” heading, the phrase “and active person registration 
status” has been added to the end of the third sentence. A new sentence has been added after the third 
sentence to specify CTEP registration requirements for ordering agents. Two new sentences have been 
added to the end of the third paragraph with instructions for contacting PMB and accessing specific 
policies and  guidelines related to agent management. 
-A new section heading titled “Investigator Brochure Availability” has been added after the “Drug 
Accountability” section in order to be consistent with the current CTEP protocol template. 
-The PMB Online Agent Order Processing (OAOP) application website URL has been updated under the 
“Useful Links and Contacts” heading. 
 
Section 16.0 (Adverse Event Reporting): 
-The fourth sentence has been updated to reflect the use of CTCAE version 5.0 for serious AE reporting. 
-In the first sentence of the second paragraph, the CTCAE version has been changed from 4.0 to 5.0, and 
the URL for the website has been updated. 
-The CTEP-AERS website URL has been added to the last sentence of the second paragraph. 
 
Section 16.2 (Additional Instructions or Exclusions): 
-The eighth bullet point has been replaced with new language regarding the reporting of death due to 
progressive disease to reflect the change in expedited reporting requirements using CTCAE version 5.0.  


3 
 
 
-The ninth bullet point has been replaced with two new bullet points regarding the reporting of secondary 
and second malignancies using CTCAE version 5.0.  
-The eleventh bullet point beginning with “The CTEP-AERS expedited reporting system…” has been 
removed, as it contains redundant and outdated information. 
-Two new bullet points have been added with instructions on reporting pregnancy loss and neonatal death 
using CTCAE version 5.0. 
 
UPDATES TO MODEL CONSENT FORM: 
 
No updates have been made to the model consent form. 
 
 
 
A replacement protocol document and model consent form have been issued. 
This study remains closed to new patient accrual. 
____________________________________________________________ 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 
 


1 
Version Date: 11/29/2018 
Update #12 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 90601 
 
A RANDOMIZED DOUBLE-BLINDED PHASE III STUDY COMPARING GEMCITABINE, 
CISPLATIN, AND BEVACIZUMAB TO GEMCITABINE, CISPLATIN, AND PLACEBO IN 
PATIENTS WITH ADVANCED TRANSITIONAL CELL CARCINOMA 
 
NCI-supplied agent(s): Bevacizumab/Placebo (NSC 704865, IND #113911) 
 
ClinicalTrials.gov Identifier: NCT00942331 
 
Study Chair 
Jonathan Rosenberg, MD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY  10065 
Tel: 646-422-4461  Fax: 646-227-2417 
rosenbj1@mskcc.org 
 
Correlative Science Co-Chair and GU 
Committee Corr. Sci. Cadre Leader 
PET Co-Chair 
 
Community Oncology Co-Chair 
Mary-Ellen Taplin, MD 
Howard McLeod, PharmD 
Preston Steen, MD 
Dana-Farber Cancer Institute 
Univ. of North Carolina 
Sanford Roger Maris Cancer Center 
Tel: 617-632-3237 
Tel: 919-966-0512 
Tel: (701) 234-6161 
mtaplin@partners.org 
hmcleod@unc.edu 
preston.steen@sanfordhealth.org 
 
GU Committee Chair 
PET Committee Chair 
GU Committee Pathologist 
Michael J. Morris, MD 
Mark Ratain, MD 
Jiaoti Huang, MD, PhD 
MSKCC 
University of Chicago 
UCLA 
Tel: 646-422-4469 
Tel: 773-702-4400 
Tel: 310-267-2264 
morrism@mskcc.org 
mratain@medicine.bsd.uchicago.edu JiaotiHuang@mednet.ucla.edu 
 
GU Faculty Statistician 
PET Faculty Statistician 
Karla Ballman, PhD 
Kouros Owzar, PhD 
Tel: 646-962-8023 
Tel: 919-681-1829 
Fax: 507-266-2477 
Fax: 919-681-8028 
kab2053@med.cornell.edu 
kouros.owzar@duke.edu 
 
 
Protocol Coordinator 
Misty Bova-Solem 
Colleen Watt 
Tel: 507-266-5364 
Tel: 773-702-4670 
Fax: 507-293-1150 
Fax: 312-345-0117 
bovasolem.misty@mayo.edu 
cboyle@uchicago.edu 
Participating Organizations:  
ALLIANCE / Alliance for Clinical Trials in Oncology (lead) 
ECOG-ACRIN / ECOG-ACRIN Medical Research Foundation, Inc. 
NRG / NRG Oncology Foundation Inc. 
SWOG / SWOG 


CALGB 90601 
Version Date: 11/29/2018 
Update #12 
2 
 
Alliance Protocol Operations Program Office 
125 S. Wacker Dr., Suite 1600 
Chicago, IL  60606 
Tel: 773-702-9171 
Fax: 312-345-0117 
www.allianceforclinicaltrialsinoncology.org 
 
Adverse Event Reporting 
https://eapps-ctep.nci.nih.gov/ctepaers/ 
 
Medidata RAVE® iMedidata Portal 
https://login.imedidata.com 
 
Alliance Biorepository at Ohio State University 
(OSU) 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 Fax: 614-293-7967 
path.calgb@osumc.edu 
 
Alliance Statistics and Data Center 
Mayo Clinic 
200 First St., SW 
Rochester, MN 55905 
 
 
CALGB 90601 Pharmacy Contact 
Myounghee Lee, PharmD, PhD 
University of Maryland 
Tel: 410-328-5468 
mlee1@umm.edu 
 
CALGB 90601 Nursing Contact 
Cesar Figueras, BSN, RN 
Tel: (734) 712-5628;  
figuerac@trinity-health.org 
 
 
Participating NCTN Group Contacts 
ECOG-ACRIN 
SWOG 
Robert Dreicer, MD, FACP 
Thomas W. Flaig, MD 
Tel: 216-445-4623 
Tel: 303-724-3808 
dreicer@ccf.org 
thomas.flaig@ucdenver.edu 
 
 
ECOG-ACRIN Coordinating Center 
SWOG Coordinating Center 
Ryan Palmer 
Dana Sparks 
Tel: 617-632-3610 
Tel: 210-450-8808 
palmer.ryan@jimmy.harvard.edu 
dsparks@swog.org 
 
The pharmacogenomic component of this study is conducted as part of the NIH Pharmacogenomics Research Network, which is 
funded through a separate U01 mechanism (see http://www.nigms.nih.gov/pharmacogenomics/research_net.html for details. 
 
 


CALGB 90601 
Version Date: 11/29/2018 
Update #12 
3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For study data submission 
Regulatory documentation must 
be submitted to the CTSU via 
the 
Regulatory 
Submission 
Portal. 
Regulatory Submission Portal: 
(Sign 
in 
at 
www.ctsu.org,  
and 
select 
the 
Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions 
with 
patients 
waiting that are unable to use 
the Portal should alert the 
CTSU 
Regulatory 
Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please 
refer 
to 
the 
patient 
enrollment section of the protocol 
for instructions on using the 
Oncology 
Patient 
Enrollment 
Network (OPEN) which can be 
accessed 
at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS.   
 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study Chair, Protocol 
Coordinator, and (where applicable) Data Manager. Contact information can be found on cover page of 
protocol 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website  
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU Website is located at https://www.ctsu.org. 
 


CALGB 90601 
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A RANDOMIZED DOUBLE-BLINDED PHASE III STUDY COMPARING GEMCITABINE, CISPLATIN, AND 
BEVACIZUMAB TO GEMCITABINE, CISPLATIN, AND PLACEBO IN PATIENTS WITH ADVANCED 
TRANSITIONAL CELL CARCINOMA 
 
Patient Eligibility 
Required Initial Laboratory Values 
Histologically or cytologically documented metastatic or  
ANC 
≥ 1500/µL 
unresectable transitional cell carcinoma of the urinary tract with  
Platelet Count 
≥ 100,000/µL 
metastatic disease or locally advanced disease (T4b,  
Bilirubin 
≤ 1.25 x ULN* 
N2, N3, or M1) (see Sec 4.1) 
AST 
≤ 2.0 x ULN 
Prior Treatment (see Sec. 4.2): 
Calc. or meas.  
 
- No prior combination chemotherapy for metastatic disease 
Creat. Clearance 
≥ 50 mL/min. 
- Radiosensitizing single agent chemotherapy is not considered systemic 
therapy 
UPC ratio < 1, or urine protein ≤ 1+, or 
24-hour urine protein ≤ 1 gram * 
- Prior neoadjuvant or adjuvant therapy is permissible, 
*See Section 4.6 
provided the interval from end of therapy to diagnosis of metastatic disease is at least 1 year. 
- ≥ 4 weeks since any radiation therapy (including palliative) or major surgery and fully recovered 
- ³ 7 days since any minor surgery such as port placement 
- ≥ 4 weeks from any intravesical therapy 
- No prior treatment with bevacizumab or other angiogenesis inhibitors. 
No known history of brain metastases (brain imaging (MRI/CT) is not required). 
No current congestive heart failure (NYHA Class 2 or higher). 
Patients with history of hypertension must be well controlled (<150/90). 
Patients on full-dose anticoagulants must be on a stable dose of warfarin and have an in-range INR or be on a stable dose of 
LMW heparin (see Section 4.3.4).  
No significant history of bleeding events within 6 months of registration (except for hematuria able to be controlled with 
endoscopic intervention) (see Section 4.3.5). 
No history of gastrointestinal perforation within 12 months of registration 
No clinically significant peripheral arterial disease  
No arterial thrombotic events within 6 months (see Section 4.3.6). 
No serious or non-healing wound, ulcer or bone fracture. 
No clinically significant peripheral neuropathy (grade ≥ 2). 
Patients that are pregnant or nursing are not eligible (see Section 4.4) 
No known hypersensitivity to Chinese hamster ovary cell products (see Section 4.3.9). 
ECOG Performance Status: 0-1. 
Age ≥ 18. 
Schema 
1 cycle = 21 days 
 
 
ARM A 
 
 
 
 
Gemcitabine 1000 mg/m2 IV on Day 1 and 
Day 8 of every cycle 
Cisplatin 70 mg/m2 IV on Day 1* 
Placebo 15 mg/kg IV on Day 1 
 
Placebo 15 mg/kg IV every 21 
days 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 cycles 
 
 
 
 
 
 
 
ARM B 
 
 
 
Gemcitabine 1000 mg/m2 IV on Day 1 and  
Day 8 of every cycle 
Cisplatin 70 mg/m2 IV on Day 1* 
Bevacizumab 15 mg/kg IV on Day 1 
 
Bevacizumab 15 mg/kg IV 
every 21 days 
 
 
 
 
 
 
 
 
 
 
 
 
* 
For patients with a creatinine clearance of ≥ 50 and < 60 mL/min, cisplatin will be administered at a dose of 35 
mg/m2 on Days 1 and 8 of each cycle, see Section 8.3. 
Treatment with gemcitabine and cisplatin should continue for a maximum of 6 cycles. Treatment with 
bevacizumab/placebo alone will continue until disease progression or unacceptable toxicity. 


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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION ................................................................................................................. 8 
1.1 
Background .............................................................................................................................. 8 
1.2 
Gemcitabine and cisplatin combination chemotherapy .............................................................. 8 
1.3 
VEGF in Bladder Cancer .......................................................................................................... 9 
1.4 
Gemcitabine, cisplatin, and bevacizumab data in bladder cancer and other solid tumors ............ 9 
1.5 
Impact of pharmacogenomic variation on benefits associated with bevacizumab, gemcitabine, 
and cisplatin therapy .............................................................................................................. 10 
1.6 
Rationale ................................................................................................................................ 11 
1.7 
Study Design .......................................................................................................................... 12 
1.8 
 Inclusion of Women and Minorities ....................................................................................... 13 
Accrual Targets ................................................................................................................................. 13 
2.0 
OBJECTIVES ...................................................................................................................... 13 
2.1 
Primary Objective................................................................................................................... 13 
2.2 
Secondary Objectives ............................................................................................................. 13 
3.0 
ON-STUDY GUIDELINES ................................................................................................. 13 
4.0 
ELIGIBILITY CRITERIA.................................................................................................. 14 
4.1 
Histologic Documentation and Stage ...................................................................................... 14 
4.2 
 Prior Treatment for TCC:....................................................................................................... 14 
4.3 
Patient History ........................................................................................................................ 14 
4.4 
Pregnancy status ..................................................................................................................... 15 
4.5 
Age and performance status .................................................................................................... 15 
4.6 
Required Initial Laboratory Values (other tests are required; see Section 6.0):......................... 15 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION .................................. 16 
5.1 
CTEP Registration Procedures ................................................................................................ 16 
5.2 
CTSU Registration Procedures ............................................................................................... 17 
5.3 
Registration Requirements ...................................................................................................... 18 
5.4 
Patient Registration/Randomization Procedures ...................................................................... 18 
5.5 
Registration to companion studies........................................................................................... 19 
5.6 
Stratification Factors: ............................................................................................................. 19 
6.0 
DATA AND SAMPLE SUBMISSION ................................................................................ 19 
6.1 
Data Submission ..................................................................................................................... 19 
6.2 
Sample submission for correlative studies ............................................................................... 22 
7.0 
REQUIRED DATA .............................................................................................................. 25 
8.0 
TREATMENT PLAN .......................................................................................................... 26 
8.1 
Duration of treatment.............................................................................................................. 26 
8.2 
Gemcitabine ........................................................................................................................... 26 
8.3 
Cisplatin ................................................................................................................................. 26 
8.4 
Bevacizumab/Placebo ............................................................................................................. 27 
8.5 
Cisplatin-induced emesis ........................................................................................................ 27 
8.6 
Aspirin ................................................................................................................................... 27 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ................................. 27 
9.1 
Hematologic Toxicity ............................................................................................................. 28 
9.2 
Hepatic Dysfunction ............................................................................................................... 29 
9.3 
Neurotoxicity ......................................................................................................................... 29 


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9.4 
Dose modifications for gastrointestinal toxicity....................................................................... 29 
9.5 
Dose modifications for Day 1 and Day 8 kidney function........................................................ 29 
9.6 
Bevacizumab/placebo dose modifications for hypertension ..................................................... 30 
9.7 
Bevacizumab/placebo dose modifications for reversible posterior leukoencephalopathy 
syndrome (RPLS) .................................................................................................................. 30 
9.8 
Bevacizumab/placebo dose modifications for thrombosis: ....................................................... 30 
9.9 
Bevacizumab/placebo dose modifications for hemorrhage/bleeding ........................................ 31 
9.10 
Dose modifications for fistula or perforation involving any organ, bowel obstruction, and 
wound dehiscence .................................................................................................................. 31 
9.11 
Bevacizumab/placebo dose modifications for proteinuria ........................................................ 32 
9.12 
Hypersensitivity and infusion reactions ................................................................................... 32 
9.13 
Surgery................................................................................................................................... 33 
9.14 
Fatigue ................................................................................................................................... 33 
9.15 
Other non-hematologic toxicities ............................................................................................ 33 
9.16 
Dose Modification for Obese Patients ..................................................................................... 33 
10.0 
CORRELATIVE SCIENCE SUBSTUDIES ....................................................................... 33 
10.1 
Angiogenic biomarker studies ................................................................................................. 34 
10.2 
Tissue-based chemotherapy resistance biomarkers .................................................................. 38 
10.3 
Evaluation of somatic mutations and copy number changes associated with treatment response
 .............................................................................................................................................. 42 
10.4 
Pharmacogenomic companion study ....................................................................................... 46 
10.5 
Evaluation of the Relationship between Intrinsic Subtype Membership and Treatment Response
 .............................................................................................................................................. 47 
11.0 
DRUG FORMULATION, AVAILABILITY AND PREPARATION ................................ 50 
11.1 
Gemcitabine (2’deoxy-2’,2’-difluorocytidine; dFDC; difluorodeoxycytidine; gemcitabine 
hydrochloride; Gemzar®) ...................................................................................................... 50 
11.2 
Cisplatin ................................................................................................................................. 51 
11.3 
 Bevacizumab (rhuMAb VEGF, Avastin®) (NSC #704865/IND #113911) .............................. 51 
12.0 
ANCILLARY THERAPY ................................................................................................... 58 
12.1 
Supportive care....................................................................................................................... 58 
12.2 
 Palliative radiation ................................................................................................................. 58 
12.3 
CALGB 90601 Policy Concerning the Use of Growth Factors ................................................ 59 
13.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE .................................. 59 
13.1 
Measurable Disease/Target Lesions ........................................................................................ 59 
13.2 
Non-target Lesions ................................................................................................................. 61 
13.3 
Cytology and Histology .......................................................................................................... 61 
13.4 
Evaluation of Best Overall Response ...................................................................................... 61 
14.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ......................................... 62 
14.1 
Duration of Treatment ............................................................................................................ 62 
14.2 
Extraordinary Medical Circumstances..................................................................................... 62 
14.3 
Crossover ............................................................................................................................... 63 
15.0 
STATISTICAL CONSIDERATIONS ................................................................................. 63 
15.1 
Endpoints ............................................................................................................................... 63 
15.2 
Stratification ........................................................................................................................... 63 
15.3 
Power Considerations ............................................................................................................. 63 
15.4 
Interim Analysis ..................................................................................................................... 63 
15.5 
Toxicity Monitoring ............................................................................................................... 64 
15.6 
Data Analysis ......................................................................................................................... 65 


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15.7 
Accrual and Follow-up ........................................................................................................... 65 
15.8 
Serum and tissue-based biomarker studies .............................................................................. 66 
15.9 
Statistical considerations for the evaluation of the effect of tobacco on bladder cancer outcomes
 .............................................................................................................................................. 68 
15.10  Pharmacogenomic analysis .................................................................................................... 69 
16.0 
ADVERSE EVENT REPORTING (AER) .......................................................................... 70 
16.1 
CALGB 90601 Reporting Requirements: ................................................................................ 71 
16.2 
Additional instructions or exclusions ...................................................................................... 72 
16.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Bevacizumab (rhuMAb 
VEGF, NSC 704865) ............................................................................................................. 73 
17.0 
REFERENCES .................................................................................................................... 80 
APPENDIX I........................................................................................................................................ 93 
APPENDIX II ...................................................................................................................................... 95 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
INTRODUCTION 
1.1 
Background 
Transitional cell carcinoma (TCC) is the fifth most common new cancer reported in the United 
States, with an incidence of 67,000 new cases per year, and about 13,000 deaths per year.1 The 
majority (70%) of TCC are superficial, without invasion of lamina propria or muscle; 
approximately 30% present with invasive or metastatic disease.2 Up to 70% of patients with 
superficial TCC recur, and one-third progress to higher grade or stage. Patients with 
progression to invasive or metastatic disease have poor survival with current therapies. 
Survival in patients with metastatic or locally advanced unresectable transitional cell 
carcinoma (TCC) of the bladder is prolonged with cisplatin-based combination chemotherapy. 
However, durable complete remissions in patients with advanced disease are rare, and median 
time to progression (TTP) is short. In an updated report of the randomized trial comparing M-
VAC with gemcitabine and cisplatin, survival at five years was 15.3% and 13%, respectively 
(p=NS).3 These results confirm that TCC is a chemotherapy-sensitive disease, and that 
improvements in first-line chemotherapy may yield improved progression-free and overall-
term survival with this disease. Addition of novel agents to standard chemotherapy may 
provide such improvements. 
1.2 
Gemcitabine and cisplatin combination chemotherapy 
Gemcitabine/cisplatin (GC) is the most commonly used first-line chemotherapy regimen in 
transitional cell carcinoma (TCC). It has largely replaced MVAC as the standard of care on the 
basis of an international phase III trial that showed similar overall survival with significantly 
less toxicity.4 Updated results demonstrated a median TTP on this trial for patients treated with 
GC of 7.7 months and median overall survival (OS) or 14.0 months.3 Recently updated results 
of this clinical trial continue to affirm similar long-term disease outcomes of these two 
regimens. This study used the 28-day regimen of gemcitabine/cisplatin, with gemcitabine 
administered on days 1, 8, and 15 at a dose of 1000 mg/m2. 
Gemcitabine and cisplatin dose and schedule: Extensive work has been done in other 
malignancies regarding the comparability and dose intensity of gemcitabine/cisplatin given on 
a 21-day and a 28-day schedule. While the 21-day schedule has not been tested in a 
randomized phase III study in urothelial carcinoma, it has been tested in non-small cell lung 
carcinoma and found to be similar in efficacy to the 28 day schedule, and associated with a 
higher dose-intensity for both drugs. Data exist suggesting that the 28-day regimen is 
associated with significant dose reduction and omission of the day 15 gemcitabine, yielding an 
average weekly dose of gemcitabine that is inferior to the 21-day regimen. With the 21-day 
regimen at a dose of 1000 mg/m2, the gemcitabine average weekly dose is approximately 588-
639 mg/m2/wk, leading to a dose intensity of 88-89%.5-8 For the four-week regimen using a 
dose of 1000 mg/m2, the gemcitabine average weekly dose is 520-600 mg/m2/wk, leading to a 
dose intensity of 69-80%. 4,9-14  Thus, more gemcitabine is administered with the three-week 
regimen due to fewer omissions and dose reductions. In addition, more frequent dosing of 
cisplatin using the 21-day schedule results in higher cisplatin dose intensity. Cisplatin average 
weekly dose (based on 70 mg/m2) ranged from 20.6 – 22.9 mg/m2/week with the 21-day 
schedule, and from 16.7-17.8 mg/m2/week with the 28-day schedule. Cisplatin dose intensity 
may be important for outcomes in bladder cancer, as a trend towards improved long-term 
survival (although not median survival), objective response, and progression-free survival was 
observed in EORTC 30924, which compared dose dense MVAC with conventional MVAC.15  
In bladder cancer, clinical outcomes with the 21-day regimen in phase II studies were similar 
to those observed with the 28-day regimen from the previous phase III study. The overall 


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response rate in urothelial carcinoma with the 21-day regimen is 45-49%, and median survival 
ranges from 9.1-13.2 months16-18 compared with a response rate of 41-57% and a median 
survival range of 10.5 to 14.3 months.4,12-14  In the Winquist study, there were a majority of 
patients with intermediate and poor risk features, which may explain the 9.1-month median 
survival. These data suggest that the 21-day regimen is legitimate to use in this context and 
compares favorably with the 28-day regimen in TCC. Given the increased dose intensity with 
the 21-day regimen, similar efficacy with this regimen, and its de facto use as the standard of 
care, this phase III trial will use this 21-day regimen as the control arm. 
1.3 
VEGF in Bladder Cancer 
The importance of angiogenesis in invasive TCC is well documented. Increased microvessel 
density has been shown to predict advanced disease and poor prognosis in TCC.19-23 Preclinical 
models in bladder cancer suggest that anti-angiogenic therapies may inhibit progression of 
bladder cancer, and that VEGF is the primary pro-angiogenic mediator of this progression.20,24-
26 Both VEGF mRNA and protein are over-expressed in advanced bladder cancer compared 
with normal bladder epithelium.27-29 In addition to its pro-angiogenic properties, recent in vitro 
experiments also suggest a role for VEGF signaling as an autocrine and paracrine growth 
factor to directly promote bladder cancer growth.30 Furthermore, retrospective evaluation of 
serum VEGF levels in the metastatic setting appears to correlate high levels with poor disease-
free survival.31 Baseline VEGF mRNA expression levels and microvessel density were found 
to be independent prognostic factors for recurrence and metastasis in 51 patients treated with 
neoadjuvant MVAC chemotherapy and cystectomy.32  
In addition to its pro-angiogenic role, elevated levels of VEGF in tumors lead to abnormal 
microvasculature. Excessive angiogenic factors recruit endothelial and perivascular cells to 
form tortuous and dilated blood vessels with poor rheological characteristics, leading to 
abnormal tumor blood flow. Elevated VEGF levels in tumors leads to increased vascular 
permeability.33 These changes lead to increased interstitial fluid pressure, which impairs the 
delivery of chemotherapy to tumor cells due to a decrease in the pressure gradient.34-36 By 
reducing VEGF levels, not only are the aberrant tumor-associated blood vessels eliminated, 
but the microvasculature also appears to be remodeled, leading to more “normal” blood vessel 
architecture. This leads to improved transvascular drug delivery directly to tumor cells. Anti-
VEGF strategies decrease interstitial fluid pressure in tumors and enhance delivery of 
chemotherapy to tumor cells, resulting in improved and prolonged responses.34 Preclinical 
studies have shown that addition of anti-VEGF strategies to TCC chemotherapy leads to 
improved responses.37-40 Addition of bevacizumab to chemotherapy has been shown in phase 
III studies to improve overall survival in lung (22% improvement) and colorectal cancer (30% 
improvement with 1st-line, and 19% improvement with 2nd-line) using different chemotherapy 
regimens, and progression-free survival in breast cancer (49% improvement).41-44  
1.4 
Gemcitabine, cisplatin, and bevacizumab data in bladder cancer and other solid tumors 
Preliminary data is available from the Hoosier Oncology Group single arm phase II trial of 
gemcitabine, cisplatin, and bevacizumab (GCB) (personal communication, C. Sweeney). 
Although the primary endpoint of this study is progression-free survival, objective response 
data is available for 30 patients. Of the 30 patients who are evaluable for response, 5 patients 
have experienced complete responses (16.7%), 19 patients have had partial responses (63.3%), 
five patients with stable disease (16.7%), and 1 with progressive disease (3.3%). 13 patients 
are not yet evaluable for response. The gemcitabine dose in the study was reduced from 1250 
mg/m2 to 1000 mg/m2 after seven thromboembolic events were observed in the first 17 
patients enrolled (58%). Of the next 26 patients, two patients experienced thromboembolism 
(8%). Cisplatin-based combination chemotherapy itself is associated with a high rate of 


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thromboembolic events in urothelial carcinoma patients, although with gemcitabine dose 
reduction appears to have reduced the risk in this patient population.45 Bleeding has not been 
observed to a significant degree in the phase II study. Gemcitabine, carboplatin, and 
bevacizumab in bladder cancer patients unfit for cisplatin is being tested at Memorial Sloan-
Kettering Cancer Center, and the investigators have not observed any significant bleeding or 
thrombotic episodes (personal communication, D. Bajorin). 
Although no complete phase II data in TCC are available for the proposed experimental 
regimen in TCC, GCB has been tested in a randomized phase III study compared with 
gemcitabine, cisplatin, and placebo in non-small cell lung carcinoma.46 In that study, 
gemcitabine was administered at a dose of 1250 mg/m2 days 1 and 8, cisplatin at a dose of 80 
mg/m2 day 1 in combination with either bevacizumab 7.5 mg/kg, bevacizumab 15 mg/kg, or 
placebo every 21 days. Bevacizumab given at both doses showed an improvement in 
progression-free survival compared to placebo. In addition, objective responses were more 
frequent in patients treated with bevacizumab. Overall survival data was not available at the 
time of the report. Arterial thrombotic events were not more frequent with the bevacizumab 
arms (5% placebo, 2% bevacizumab 7.5 mg/kg, and 3% bevacizumab 15 mg/kg), and venous 
thrombotic events were similar in both arms (6% placebo, 7% bevacizumab 7.5 mg/kg, and 
7% bevacizumab 15 mg/kg). 
There are also data available for safety from a randomized phase II trial of GCB vs. GC plus 
placebo in 95 patients with malignant mesothelioma.47 Patients in this trial were treated with 
gemcitabine 1250 mg/m2 IV days 1 and 8 every 21 days, cisplatin 75 mg/m2 day 1, and 
placebo or bevacizumab 15 mg/kg every 21 days. There was no statistically significantly 
increased risk associated with GCB over GC except for hypertension (28% vs. 6%) and 
epistaxis (37% [4% grade 3] vs. 6%). No visceral perforations were observed, and thrombotic 
complications were less than 10% in both arms.  
1.5 
Impact of pharmacogenomic variation on benefits associated with bevacizumab, 
gemcitabine, and cisplatin therapy 
The regulatory region of VEGF contains many transcription factor binding sites and its 
transcriptional as well as translational regulation appears to be quite complex. Over the past 
few years, several VEGF variants have been identified in the VEGF promoter and UTRs, and 
some of the variants have been associated with altered VEGF levels. In a few retrospective 
studies, VEGF polymorphisms have also been linked to altered disease risk.48,49 Since 
bevacizumab directly neutralizes VEGF, it is quite likely that VEGF variants that are 
associated with higher VEGF levels could influence the drug response to such a therapy. One 
such common variant (936 C>T) in the 3’UTR of the VEGF gene has been associated with 
VEGF plasma levels. Individuals with CC genotype had significantly higher VEGF levels than 
individuals with CT or TT genotypes, and about 71% of a Caucasian population studied 
carried the CC genotype.49  
Gemcitabine pharmacology is quite complex with its various metabolites responsible for a 
wide array of mechanisms that lead to its cytotoxicity. Briefly, gemcitabine is first transported 
across the plasma membrane via active nucleoside transporters. It is subsequently activated by 
deoxycytidine kinase intracellularly to its monophosphate metabolite, and the monophosphate 
metabolite can be phosphorylated further to di- and tri-phosphate metabolites by deoxycytidine 
kinase and nucleoside diphospho kinase. Gemcitabine is degraded predominantly by cytidine 
deaminase to difluorodeoxyuridine. Given the reported variability in gemcitabine 
pharmacology and clinical response, and emerging information regarding genetic variants in 
different genes (CDA, DCK, DCTD, SLC29A1, SLC28A1, SLC29A2) involved in gemcitabine 
metabolism, degradation, and transport, it would be prudent to explore the potential role such 
variants might play in gemcitabine drug response.50-52 


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The pharmacology of cisplatin is less well-defined. However, all platinum agents appear to be 
influenced by intracellular levels of the glutathione S-transferase (GST) family.48 This 
multigene family is a key component of detoxifying pathways and is responsible for 
conjugation of reactive radicals. The frequency of a deletion in GST M1 (frequency 53%) and 
a single nucleotide polymorphism in GST P1 (AA frequency 51%) will be evaluated to 
determine the influence of detoxification genotype on cytotoxicity and outcome.53 In addition, 
genetic variations in XRCC1 have been associated with response to platinum agents.54 The 
hypothesis is that patients with the XRCC1 Arg/Arg genotype (frequency 41%) will be more 
resistant to cisplatin therapy. 
In addition to specific hypothesis testing for the above candidate genes, this study will also 
provide the framework for hypothesis generating investigations of genotype and/or haplotype 
in additional candidate genes of putative importance to gemcitabine, cisplatin, or bevacizumab 
drug response. 
1.6 
Rationale 
Based on the evidence that angiogenesis and VEGF play an important role in TCC 
progression, that TCC is a chemosensitive disease, and the pre-clinical data that bevacizumab 
improves chemotherapy delivery, locally advanced or metastatic TCC represents an 
opportunity to test anti-VEGF strategies. Testing anti-angiogenic agents in the first-line setting 
in combination with standard chemotherapy is likely to have the largest impact on TCC 
outcomes. Inhibition of VEGF using an anti-VEGF monoclonal antibody inhibits the growth 
of a number of human cancers in nude mice.55 Bevacizumab, a recombinant humanized murine 
monoclonal antibody against VEGF, has shown significant clinical activity in other cancer 
types. It has been successfully combined with gemcitabine and cisplatin in other diseases, and 
proven safe.  
Survival in patients with metastatic or locally advanced unresectable TCC of the bladder is 
prolonged with cisplatin-based combination chemotherapy. However, durable complete 
remissions in patients with advanced disease are rare, and median time to progression (TTP) is 
short. In an updated report of the randomized trial comparing M-VAC with gemcitabine and 
cisplatin, survival at five years was 15.3% and 13%, respectively (p = NS).3 These results 
confirm that TCC is a chemotherapy-sensitive disease, that gemcitabine and cisplatin is an 
appropriate therapy, and that improvements in first-line chemotherapy may yield improved 
progression-free and overall-term survival with this disease. Recently reported data from the 
randomized phase III study of gemcitabine and cisplatin or gemcitabine, cisplatin, and 
paclitaxel did not show a significant advantage for the triplet combination.56 As a result, 
gemcitabine and cisplatin remains a standard of care for patients with advanced TCC. If the 
addition of bevacizumab improves progression-free and overall survival, it will change the 
standard of care in this disease. 
Reported survival for patients with metastatic TCC treated on chemotherapy trials varies 
widely. This variation may be explained by pre-treatment disease- and patient-related factors. 
To define the effect of pre-treatment patient characteristics on clinical outcome, Bajorin 
conducted a multivariate analysis evaluating eighteen variables in 203 patients treated with 
MVAC. In this analysis, KPS < 80% and presence of visceral metastases were independently 
prognostic of survival. The presence of both adverse features was associated with a median 
survival of 9.3 months; the presence of one adverse feature was associated with a median 
survival of 13.4 months; and the presence of no adverse prognostic features was associated 
with a median survival of 33 months.57  These factors were confirmed in the long term follow-
up of the randomized phase III trial of gemcitabine/cisplatin vs. MVAC in metastatic TCC.3 
As a result, because eligibility will be limited to patients with KPS > 80% (ECOG 
performance status 0-1), randomization will be stratified in this study according to the 


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presence of visceral metastasis. In addition, patients will be stratified by prior chemotherapy 
for muscle-invasive TCC as neoadjuvant or adjuvant therapy. 
This randomized phase III study will compare standard GC chemotherapy to GCB 
chemotherapy with overall survival as the primary endpoint. This study will have early 
stopping rules for futility of the experimental arm to ensure that excessive numbers of patients 
are not exposed to an obviously inferior regimen. In addition, real-time toxicity monitoring 
with monthly conference calls will be incorporated into the protocol to monitor for excess 
toxicity in the GCB arm. Blood will be collected for all patients at baseline, prior to cycle 4, at 
the end of protocol treatment, and at the time of progression to evaluate the predictive value of 
VEGF plasma levels in a large study of metastatic TCC patients treated with chemotherapy 
with or without bevacizumab. Based on the Hoosier Oncology Group data suggesting 
excessive frequency of thromboembolic events with gemcitabine 1250 mg/m2 in combination 
with bevacizumab in TCC, the wide use of gemcitabine 1000 mg/m2 in bladder cancer on a 3 
week schedule, and the improved dose intensity of the 3 week schedule compared to the four 
week schedule, the dose of gemcitabine will be 1000 mg/m2 administered on days 1 and 8, 
with cisplatin 70 mg/m2 on day 1 every three weeks. 
Progression free survival is a secondary endpoint of this study. A non-biased assessment of 
this endpoint necessitates that this trial be a placebo-controlled, double-blinded study. Previous 
randomized clinical trials of advanced TCC have treated patients for a maximum of six 
chemotherapy cycles. Therefore, this trial will allow administration of up to six cycles of 
chemotherapy. Bevacizumab/placebo as maintenance therapy may be administered until 
progression. 
Patients with creatinine clearance 50 mL/min or greater will be eligible for this study. Split 
dosing of cisplatin is a reasonable approach for patients with creatinine clearances ≥ 50 and < 
60 mL/min.199, 200 The use of split dosing is associated with no obvious increase in renal 
dysfunction or other toxicity in phase II studies. Therefore, for those patients with creatinine 
clearances ≥ 50 and < 60 mL/min, the cisplatin dose will be split to 35 mg/m2 on day 1 of the 
cycle, and again on day 8 with pre- and post-hydration according to institutional guidelines. 
Dosing for patients with a creatinine clearance ≥ 60 mL/min will remain at 70 mg/m2 on day 1. 
There is increasing evidence suggesting that germline polymorphisms related to anticancer 
drug metabolism, transport, and resistance correlate with drug response. Furthermore, 
germline polymorphisms related to therapeutic targets and/or therapeutic pathways might also 
help predict therapeutic outcome.58,59 Assays for genetic variants will be performed for VEGF 
(Bevacizumab) and CDA, DCK, DCTD, SLC29A1, SLC28A1, SLC29A2 (gemcitabine) and 
GST P1, GST M1, XRCC1 (cisplatin). These candidate genes have been chosen based on their 
potential influence on activation, degradation, transport disposition or cytotoxicity of 
gemcitabine, cisplatin, and bevacizumab. Additional genes or variants of interest might also be 
explored as new information relevant to the study emerges. The primary hypothesis of the 
pharmacogenomic substudy is that patients with the VEGF CC genotype will receive 
significantly greater benefit (OS, PFS) from anti-VEGF therapy.  
1.7 
Study Design 
Patients will be randomized in a 1:1 allocation ratio between gemcitabine, cisplatin, and 
bevacizumab and gemcitabine, cisplatin, and placebo. In the absence of unacceptable toxicity 
or progression, patients will receive a maximum of 6 cycles of chemotherapy. If patients do 
not have disease progression after six cycles, then patients will continue on 
bevacizumab/placebo until disease progression or until patients experience unacceptable 
toxicity. Study participants will remain blinded at progression with no crossover permitted. 


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1.8 
Inclusion of Women and Minorities 
In selecting patients for study in this protocol, we have taken due notice of NIH/ADAMHA 
policies concerning inclusion of women and minorities in clinical research populations. We 
expect that the study population will be fully representative of the range of patients seen at 
Alliance participating institutions, without exclusion as to age, gender, or ethnic background. 
The agents used in this trial may be teratogenic, especially in the first trimester. Therefore, 
pregnant women are excluded from participation in this study. 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
7 
+ 
14 
= 
21 
Not Hispanic or Latino 
139 
+ 
340 
= 
479 
Ethnic Category: Total of all subjects 
146 
+ 
354 
= 
500 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
7 
= 
7 
Asian 
0 
+ 
7 
= 
7 
Black or African American 
14 
+ 
21 
= 
35 
Native Hawaiian or other Pacific Islander 
0 
+ 
7 
= 
7 
White 
132 
+ 
312 
= 
444 
Racial Category: Total of all subjects 
146 
+ 
354 
= 
500 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To determine if patients with advanced transitional cell carcinoma treated with bevacizumab, 
gemcitabine and cisplatin will have increased overall survival when compared to patients 
treated with gemcitabine, cisplatin, and placebo. 
2.2 
Secondary Objectives 
2.2.1 
To compare the progression-free survival of these two regimens in patients with 
advanced transitional cell carcinoma.  
2.2.2 
To compare the proportion of patients who experience an objective response on each 
regimen. 
2.2.3 
To compare the grade 3 and greater toxicities in patients treated on the two regimens.  
[See Section 10.0 correlative sciences and pharmacogenetic substudy objectives.] 
3.0 
ON-STUDY GUIDELINES 
The following guidelines are to assist physicians in selecting patients for whom protocol therapy is 
safe and appropriate. Physicians should recognize that the following may seriously increase the risk 
to the patient entering this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent 


CALGB 90601 
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14 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
• 
Patients with a "currently active" second malignancy other than non-melanoma skin cancers. 
Patients are not considered to have a "currently active" malignancy if they have completed any 
necessary therapy and are considered by their physician to be at less than 30% risk of relapse.  
• 
Participants in this study must agree to use adequate contraception for the duration of treatment 
and for at least three months following the completion of protocol therapy. 
4.0 
ELIGIBILITY CRITERIA 
4.1 
Histologic Documentation and Stage 
Patients must have histologically or cytologically documented metastatic or unresectable 
transitional cell (urothelial) carcinoma of the urinary tract (renal pelvis, ureter, bladder, 
prostate, or urethra), with metastatic or locally advanced disease (T4b, N2, N3, or M1). 
Patients must not be candidates for potentially curative surgery or radiotherapy. 
For patients that have had surgical resection prior to study enrollment, residual or unresected 
disease (measurable and/or unmeasurable) must be evident on post-surgical scans. 
4.2 
Prior Treatment for TCC:  
• 
Patients may not have received combination systemic chemotherapy for metastatic 
disease.  
• 
For the purposes of this study, radiosensitizing single agent chemotherapy is not 
considered prior systemic therapy.  
• 
Prior neoadjuvant or adjuvant systemic chemotherapy is permissible provided the interval 
from end of therapy to diagnosis of metastatic disease is at least 1 year. 
• 
≥ 4 weeks since any prior radiation (including palliative) or major surgery and fully 
recovered. 
• 
³ 7 days since any minor surgery such as port placement 
• 
≥ 4 weeks since any intravesical therapy 
• 
No prior treatment with bevacizumab or other angiogenesis inhibitors. 
4.3 
Patient History 
4.3.1 
No known history of brain metastases: Brain imaging (MRI/CT) is not required. 
4.3.2 
No current congestive heart failure: New York Heart Association Class II, III or IV. 
4.3.3 
Patients with history of hypertension must be well controlled (< 150/90) on a regimen 
of anti-hypertensive therapy. 
4.3.4 
Patients on full-dose anticoagulants must be on a stable dose of warfarin and have 
an in-range INR (usually between 2 and 3) or be on a stable dose of LMW heparin. 
Patients receiving anti-platelet agents are also eligible. In addition, patients who are on 
daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible. 
4.3.5 
No significant history of bleeding events or GI perforation. 
• 
Patients with a history of a significant bleeding episode (e.g. hemoptysis, upper or 
lower GI bleeding, grade 3 or 4 gross hematuria unable to be controlled by trans-
urethral resection of the bladder tumor) within 6 months of registration are not 
eligible.  


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15 
• 
Patients with a history of GI perforation within 12 months of registration are not 
eligible. 
• 
Patients with a history of peritoneal carcinomatosis are not eligible. 
4.3.6 
No arterial thrombotic events within 6 months of registration, including transient 
ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, 
unstable angina or angina requiring surgical or medical intervention in the past 6 months, 
or myocardial infarction (MI). Patients with clinically significant peripheral artery 
disease (i.e., claudication on less than one block) are ineligible.  
Patients who have experienced a deep venous thrombosis or pulmonary embolus 
within the past 6 months must be on stable therapeutic anticoagulation to be enrolled to 
this study. 
4.3.7 
No serious or non-healing wound, ulcer or bone fracture. 
4.3.8 
No sensory or motor peripheral neuropathy ≥ grade 2. 
4.3.9 
Patients with known hypersensitivity to Chinese hamster ovary cell products or 
other recombinant human antibodies are not eligible. 
4.4 
Pregnancy status 
Patients that are pregnant or nursing are not eligible. Women of child bearing potential 
must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 72 hours prior to registration. This is because DNA alkylating 
agents are known to be teratogenic, and the effects of gemcitabine, cisplatin, and bevacizumab 
on a developing fetus at the recommended therapeutic doses are unknown.  
For women of child-bearing potential with an elevated beta-HCG that is believed to be 
related to cancer and not pregnancy, a negative trans-vaginal ultrasound and gynecological 
examination are required. 
Women of child-bearing potential include any female who has experienced menarche and who 
has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral 
oophorectomy) or is not postmenopausal [defined as amenorrhea ³ 12 consecutive months; or 
women on hormone replacement therapy (HRT) with documented serum follicle stimulating 
hormone (FSH) level > 35mIU/mL]. Even women who are using oral, implanted or injectable 
contraceptive hormones or mechanical products such as an intrauterine device or barrier 
methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or 
where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential. 
4.5 
Age and performance status 
4.5.1 
Age ≥ 18 
4.5.2 
ECOG performance status 0-1 (or KPS ≥ 80) 
4.6 
Required Initial Laboratory Values (other tests are required; see Section 6.0): 
ANC 
≥ 1500/µL 
Platelet count 
≥ 100,000/µL 
Calculated*** or measured 
 creatinine clearance 
 
≥ 50 mL/minute  
Bilirubin 
≤ 1.25 x upper limits of normal** 
AST 
£ 2.0 x upper limits of normal 
Urine protein to creatinine ratio* < 1.0 or Urine protein ≤ 1+ or  
24-hour Urine protein ≤ 1 gram 


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16 
* 
See Appendix II for information regarding the calculation of UPC ratio. 
** 
For patients with Gilbert's Disease, ≤ 2.5 X ULN is allowed. 
*** Modified Cockroft and Gault formula; see below 
Modified Cockcroft and Gault Formula for Estimated Creatinine Clearance (CLcr) 
For Serum Creatinine Concentration (Sr Cr) in mg/dL: 
 
Clcr (mL/min) = 
(140 - age) (actual weight)a 
 
(72) (Sr Cr) 
a 
Age in years and weight in kilograms  
For females, use 85% of calculated Clcr value 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION 
5.1 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per 
registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
a 
a 
 
 
Financial Disclosure Form 
a 
a 
a 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
a 
a 
a 
 
HSP/GCP training 
a 
a 
a 
 
Agent Shipment Form (if applicable) 
a 
 
 
 
CV (optional) 
a 
a 
a 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs 
and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the 
FDA Form 1572 in RCR to allow the following: 


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17 
•Added to a site roster 
•Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
•Act as the site-protocol PI on the IRB approval 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
5.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
•     An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS 
in an automated process. Signatory Institutions must submit a Study Specific Worksheet for 
Local Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study 
locally.  The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution must inform 
the CTSU which CIRB-approved institutions aligned with the Signatory Institution are 
participating in the study. 
5.2.1 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the CALGB 90601 protocol page 
located on the CTSU members’ website. Permission to view and download this protocol 
and its supporting documents is restricted and is based on person and site roster 
assignment housed in the CTSU RSS. 
•Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
•Click on the Protocols tab in the upper left of your screen 
•Click on the Alliance link to expand, then select trial protocol CALGB 90601. 
•Click on the Site Registration Documents link 


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18 
5.2.2 
Requirements for CALGB 90601 Site Registration: 
•CTSU IRB Certification (for sites not participating via the NCI CIRB) 
•CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  
5.2.3 
Submitting Regulatory Documents:  
Submit completed forms along with a copy of your IRB Approval (for sites not 
participating via the NCI CIRB), Model Informed Consent (for sites not participating via 
the NCI CIRB), and any other required documentation (see above) to the CTSU 
Regulatory Office, where they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
5.2.4 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
Click on the Regulatory tab at the top of your screen 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go 
5.3 
Registration Requirements 
Informed Consent: The patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedures to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. 
Human protection committee approval of this protocol and a consent form is required. 
5.4 
Patient Registration/Randomization Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website at 
https://www.ctsu.org. 
Prior to accessing OPEN, site staff should verify the following: 
•All eligibility criteria have been met within the protocol stated timeframes.  
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.   Please print this confirmation for your records.  


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To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the 
protocol specific funding page on the CTSU members’ website for additional information. 
Timely entry of completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
5.5 
Registration to companion studies 
There are two substudies within CALGB 90601. These substudies must be offered to all 
patients enrolled on CALGB 90601 (although patients may opt not to participate). The 
substudies included within CALGB 90601 are: 
• 
Correlative science studies: CALGB 150609 (Sections 10.1-10.3) 
• 
Pharmacogenomic studies: CALGB 60707 (Section 10.4) 
If a patient answers “yes” to “I agree that my specimens may be used for the research studies 
described above.” (Question #1) in the Model Consent, s/he has consented to participate in the 
biomarker studies described in Sections 10.1 through 10.3. The patient should be registered to 
CALGB 150609 at the same time that s/he is registered to the treatment trial (90601) and 
samples submitted per Sections 6.2.1 and 6.2.2. 
If a patient answers “yes” to “I agree that my blood may be used for the genetic research 
studies described above” (Question #2) in the Model Consent, s/he has consented to participate 
in the studies described in Section 10.4. Patients should be registered to CALGB 60707 at the 
same time that they are registered to 90601. Samples should be submitted per Section 6.2.3. 
5.6 
Stratification Factors:  
5.6.1 
Presence of visceral metastases (defined as lung, liver, bone, splenic, or intra-abdominal 
metastases). 
a) no 
b) yes 
5.6.2 
Prior chemotherapy for treatment of TCC, including adjuvant, neoadjuvant, and 
single agent radiosensitizers. 
a) no 
b) yes 
6.0 
DATA AND SAMPLE SUBMISSION 
6.1 
Data Submission 
As of Update #12 to the protocol, this study will use Medidata Rave® for remote data capture 
(RDC) of all future data collection. All data originally received by the Alliance and Statistics 
and Data Center (SDC) (either electronically using the “Print and/or Submit to CALGB” 
button [i.e. Teleform form] or by mail) has been transferred to Medidata Rave ® and can be 
accessed via the Medidata Rave ® system. If necessary, data originally submitted to the SDC 
electronically (or by mail) can be amended via the Medidata Rave ® system. 
The Rave system can be accessed through the iMedidata portal at https://login.imedidata.com. 
For additional information regarding account setup or training, please visit the training section 
of the Alliance website. Forms should be submitted in compliance with the table below, and a 
copy of the All Forms Packet can be downloaded from the Alliance and CTSU websites. 


CALGB 90601 
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20 
Site personnel with Rave roles assigned on the appropriate roster may receive a study 
invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata page. 
Please note, site users will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed. Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. Personnel who did not receive an invitation should contact the Alliance 
Service Center. 
Users who have not previously activated their iMedidata/Rave account at the time of an initial 
site registration approval for a study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website’s Rave tab under the Rave Resource Materials heading (Medidata Account Activation 
and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on 
the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.


CALGB 90601 
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21 
Data Submission: Submit forms at the following intervals: 
Form 
Submission Schedule 
 
Baseline  
 
 
 
C-1760 
C-2078 
C-816 
 
Report 
CALGB 90601 Registration Worksheet 
CALGB 90601 Eligibility Checklist 
CALGB 90601 On Study Form 
CALGB 90601 Charlson Index Form 
CALGB 90601 Solid Tumor Measurement Form 
(Baseline) 
Baseline Scan Reports* 
Within two weeks of registration 
 
Treatment 
 
C-1764 
C-1765 
CALGB 90601 Treatment Form 
CALGB 90601 Adverse Event Form† 
Every cycle during protocol 
therapy. 
 
 
 
C-817 
CALGB 90601 Solid Tumor Measurement Form 
(Follow Up) 
Every 3 cycles during protocol 
therapy and after any scan done at 
physician’s discretion. 
 
 
 
C-1767 
Report 
CALGB 90601 Follow Up Form  
Follow Up Scan Reports* 
Every 3 cycles and at the end of 
protocol treatment. 
 
 
 
C-1766 
CALGB 90601 Adverse Event Form  (Thromboembolic 
Events)† 
Within 24 hrs of knowledge of ≥ 
grade 3 thromboembolic event. 
 
 
 
 
Follow-up (after end of protocol treatment) 
C-1767 
CALGB 90601 Follow Up Form 
Every 3 months until progression, then 
every 6 months until 7 years after 
randomization. In addition, when new 
primary or secondary malignancies 
occur, and at death. 
 
 
 
C-817 
 
Report 
CALGB 90601 Solid Tumor Measurement Form 
(Follow Up) 
Follow Up Scan Reports* 
Submit anytime scans are done until 
progression or initiation of non-protocol 
treatment. 
 
 
 
 
Other 
 
C-1962 
CALGB 90601 Tobacco Use Questionnaire** 
Within 2 weeks of registration and after 
Day 1 of Cycle 4. 
* 
Submit copies of all required reports to confirm eligibility and restaging results. 
** For patients who consent to sub-study CALGB 150609. 
† 
Institutions that do not submit adverse event forms in a timely manner may be 
denied future registrations to this study (see Section 15.5). 
Common Toxicity Criteria: This study will use the NCI Common Terminology Criteria for 
Adverse Events version 3.0 for routine toxicity reporting on study forms. However, adverse events 
reported via CTEP-AERS must use CTCAE version 5.0 (See Section 16.0). 


CALGB 90601 
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22 
6.2 
Sample submission for correlative studies  
All participating institutions must ask patients for their consent to participate in the correlative 
substudies planned for CALGB 90601, although patient participation is optional. Biomarker 
and pharmacogenomic studies will be performed. Rationale and methods for the scientific 
components of these studies are described in Section 10.0. For patients who consent to 
participate, tissue and blood will be collected at the following time points for these studies: 
 
Within 60 
days after 
registration 
Prior to 
treatment 
Prior to 
chemotherapy on 
Day 1 of Cycle 4* 
At the end of 
all protocol 
treatment** 
At 
progression
** 
Tissue blocks1 
X 
 
 
 
 
 
Number and volume of tubes to draw 
EDTA plasma1 
(lavender top) 
 
3 x 6 mL 
3 x 6 mL 
3 x 6 mL 
3 x 6 mL 
Citrated 
plasma1 
(light blue top) 
 
4 x 2.7 mL 
4 x 2.7 mL 
4 x 2.7 mL 
4 x 2.7 mL 
Serum1 
(red/gray top) 
 
2 x 6 mL 
2 x 6 mL 
2 x 6 mL 
2 x 6 mL 
Whole blood2 
(EDTA/lavender 
top) 
1 x 10 mL 
 
 
 
 
1 
Tissue and blood samples to be used for biomarker studies (150609) 
2 
To be used for pharmacogenomic assays (60707).  
* 
Samples may be collected up to 48 hours prior to chemotherapy. 
** 
Patients for whom the end of treatment occurs within 28 days of documented 
progression do not need to have samples submitted twice at this time point. 
Specimen submission using the Alliance Biospecimen Management System  
Use of the Alliance Biospecimen Management System (BioS) is mandatory and all 
specimens must be logged and shipped via this system.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. 
Authorized 
individuals 
may 
access 
BioMS 
at 
the 
following 
URL:  
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers (Safari, 
Firefox, Internet Explorer). For information on using the BioMS system, please refer to the 
‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, and training 
videos. To report technical problems, such as login issues or application errors, please contact: 
1-855-55-BIOMS or Bioms@alliancenctn.org. For assistance in using the application or 
questions or problems related to specific specimen logging, please contact: 1-855-55-BIOMS 
or Bioms@alliancenctn.org. 
After logging collected specimens in BioMS, the system will create a shipping manifest.  This 
shipping manifest must be printed and placed in the shipment container with the specimens. 
All submitted specimens must be labeled with the protocol number (90601), Alliance patient 
number, patient’s initials and date and type of specimen collected (e.g., serum, whole blood). 


CALGB 90601 
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23 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method of 
shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Shipment on Monday through Friday by overnight service to assure receipt is encouraged. If 
shipping on Friday, FedEx or UPS must be used and the air bill must be marked “For Saturday 
delivery.” Do not ship specimens on Saturdays. 
All specimens should be sent to the following address: 
Alliance Biorepository 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH  43240 
Tel: 614-293-7073  Fax: 614-293-7967 
6.2.1 
Blood samples 
For patients who consent to participate, plasma and serum samples will be used for the 
biomarker analyses described in Sections 10.1 and 10.3.  
For EDTA plasma, collect 18 mL of peripheral venous blood in three 6 mL EDTA 
(lavender-top) tubes prior to the initiation of treatment, then 18 mL prior to chemotherapy 
on Day 1 of Cycle 4, at the end of treatment, and, if more than 28 days apart, at 
progression. The tube(s) should be inverted several times to mix the EDTA and 
refrigerated until shipped on cool pack by overnight mail to the Alliance Biorepository at 
OSU. The samples should be shipped the same day that the blood is drawn. 
For citrated plasma, collect 10.8 mL of peripheral venous blood in four 2.7 mL citrate 
(light blue-top) tubes prior to the initiation of treatment, then 10.8 mL prior to 
chemotherapy on Day 1 of Cycle 4, at the end of treatment, and, if more than 28 days 
apart, at progression. The tube(s) should be inverted several times to mix the citrate and 
refrigerated until shipped on cool pack by overnight mail to the Alliance Biorepository at 
OSU. The samples should be shipped the same day that the blood is drawn. 
For serum, collect 12 mL of venous blood in two 6 mL serum separator (red/gray-top) 
tubes prior to the initiation of treatment, then 12 mL prior to chemotherapy on Day 1 of 
Cycle 4, at the end of treatment, and, if more than 28 days apart, at progression. Gently 
invert 5 times to mix clot activator with blood. Let blood clot for up to one hour. Observe 
a dense clot. Centrifuge at 1300g for 10 minutes. The sample should be refrigerated until 
shipped on cool pack by overnight mail to the Alliance Biorepository at OSU. The 
sample should be shipped the same day that the blood is drawn.  
6.2.2 
Submission of paraffin blocks of archived TCC tumors 
For patients who consent to participate, tumor blocks will be used for the analyses 
described in Section 10.2. 
Paraffin blocks of tissue obtained from archival TCC tumor specimens from primary 
and/or metastatic sites should be sent to the Alliance Biorepository at OSU. Please 
specify the source of the tumor block (primary or metastatic site). Submit one block of 
tumor tissue and one block of normal tissue. 
The Alliance has instituted special considerations for the small percentage (5%) of 
hospitals whose policy prohibits long-term storage of blocks, and the smaller percentage 
(4%) of hospitals whose policies prohibit release of any block. If, due to institutional 


CALGB 90601 
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24 
policy, a block cannot be sent, please call the Alliance Biorepository at OSU at 614-293-
7073 to obtain a protocol to cut the sections at your institution. 
The goal of the Alliance Biorepository at OSU is to provide investigators with quality 
histology sections for their research while maintaining the integrity of the tissue. All 
paraffin blocks that are to be stored at the Alliance Biorepository at OSU will be vacuum 
packed to prevent oxidation and will be stored at 4º C to minimize degradation of cellular 
antigens. For these reasons it is preferred that the Alliance Biorepository at OSU bank the 
block until the study investigator requests thin sections. Please contact the Alliance 
Biorepository at OSU if additional assurances with your hospital pathology department 
are required. 
6.2.3 
Blood submission (for pharmacogenomic studies) 
For patients who consent to participate, whole blood samples will be used for the 
pharmacogenomic studies described in Section 10.4. This sample should be collected 
prior to the initiation of protocol treatment. 
Collect 10 mL of peripheral venous blood in an EDTA (purple-top) tube. The tube should 
be inverted several times to mix the EDTA and refrigerated until shipped on cool pack by 
overnight mail to the Alliance Biorepository at OSU. The sample should be shipped the 
same day that the blood is drawn.  
 
 


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25 
7.0 
REQUIRED DATA 
Guidelines for Pre-Study Testing  
To be completed within 16 DAYS before registration: 
- 
All blood work, EKG, history and physical. 
To be completed within 28 DAYS before registration: 
- 
CT Scan of chest/abd/pelvis, OR CT chest plus MRI abd/pelvis  
To be completed within 42 DAYS before registration: 
- 
Bone scan (or FDG-PET) 
 
Prior to 
Registration 
Day 1 of each 
cycle* 
Day 8 of each 
cycle 
Post Treatment 
Follow up** 
Tests & Observations 
 
 
 
 
History and Progress Notes 
X 
X 
 
X 
Physical Examination 
X 
X 
 
X 
Pulse, Blood Pressure 
X 
X 
 
 
Height 
X 
 
 
 
Weight/BSA*** 
X 
X 
 
 
Performance Status 
X 
X 
 
 
Tumor Measurements 
X 
A 
 
X 
Drug Toxicity Assessment 
 
X 
 
 
Laboratory Studies 
 
 
 
 
CBC, Differential, Platelets 
X 
X 
B 
 
Serum Creatinine, BUN 
X 
X 
B 
 
AST, Alk. Phos., Bili, LDH 
X 
X 
 
 
Albumin 
X 
X 
 
 
Serum or Urine HCG 
C 
 
 
 
Urinalysis/Dipstick 
X 
D 
 
 
Staging 
 
 
 
 
Bone Scan 
X (1) 
E (1) 
 
F (1) 
CT Scan of chest/abd/pelvis, OR CT 
chest plus MRI abd/pelvis 
X (2) 
E (2) 
 
F (2) 
Correlative studies† 
 
Plasma and serum samples 
See Section 6.2. 
Tissue block/slides and 
pharmacogenomics samples 
See Section 6.2. 
* 
Pre-registration tests, observations and laboratory studies completed within 14 days prior to the first day of treatment need not 
be repeated. Labs and physical exam may be obtained up to 24 hours prior to protocol therapy for all other cycles.  
** At least every 3 months until evidence of progression or relapse for a maximum of 7 years after registration. After 
progression, patients are to be followed for survival every 6 months until 7 years after registration. 
*** Drug dosages need not be changed unless the calculated dose changes by ³ 10%. 
† 
For those patients who consent to participate in one or both companion substudies (see Section 6.2) 
A 
Within 2 days prior to each gemcitabine/cisplatin treatment if accessible to physical examination. 
B 
Only required for patients receiving gemcitabine and/or cisplatin 
C 
For women of childbearing potential (see Section 4.4) 
D 
Required only for patients who have not discontinued bevacizumab/placebo. All patients receiving bevacizumab/placebo will 
have a urinalysis or urine dipstick performed within 48 hours prior to every bevacizumab/placebo dose; if urine protein is ≥ 
2+, 24-hour urine collection or UPC ratio will be required (see Section 9.11).  
E 
Every 3 cycles (beginning prior to Cycle 4) until evidence of progression, relapse or initiation of non-protocol therapy. Scans 
may be done up to 7 days prior to beginning a cycle. Confirmatory scans should also be obtained at least 4 weeks following 
documentation of objective response (see Section 13.0). Response assessment should include assessment of all sites of 
disease and use the same imaging method as was used at baseline. 
F 
Staging scans must be repeated after the end of protocol treatment unless performed within the prior 4 weeks. Thereafter, 
every 3 months until disease progression or initiation of non-protocol therapy for a maximum of 7 years following 
registration. 
1 
FDG-PET scans may substitute for bone scans at baseline evaluation. Follow up bone scan or FDG-PET scans are only 
necessary for patients with bone metastases as the only site of evaluable for metastatic disease and are optional for other 
patients. 
2 
Diagnostic CT performed with both IV and oral contrast, and the CT acquired with 5 mm or less slice thickness. 


CALGB 90601 
Version Date: 11/29/2018 
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26 
8.0 
TREATMENT PLAN 
Protocol treatment is to begin within 14 days of randomization. Questions regarding treatment 
should be directed to the Alliance Study Chair. 
This is a randomized, double-blind trial. Initial blinded, patient-specific clinical supplies of 
bevacizumab/ placebo will be requested by the Alliance Statistics and Data Center at the time of 
randomization and should arrive at the clinical site within approximately seven to ten days of 
randomization (see Section 11.3). 
It is acceptable for individual chemotherapy doses to be delivered ≤ a 24-hour (business day) 
window before and after the protocol-defined date for Day 1 of a new cycle. For example, if the 
treatment due date is a Friday, the window for treatment includes the preceding Thursday through 
the following Monday. In addition, patients are permitted to have a new cycle of chemotherapy 
delayed up to 7 days for major life events (e.g., serious illness in a family member, major holiday, 
vacation that cannot be rescheduled) without this being considered a protocol violation. 
Documentation to justify this delay should be provided. 
Each cycle is 21 days 
 
 
ARM A 
 
 
 
 
Gemcitabine 1000 mg/m2 IV on Day 1 and  
Day 8 of every cycle 
Cisplatin 70 mg/m2 IV on Day 1* 
Placebo 15 mg/kg IV on Day 1 
 
Placebo 15 mg/kg IV every 
21 days 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 cycles 
 
 
 
 
 
 
 
ARM B 
 
 
 
Gemcitabine 1000 mg/m2 IV on Day 1 and 
Day 8 of every cycle 
Cisplatin 70 mg/m2 IV on Day 1* 
Bevacizumab 15 mg/kg IV on Day 1 
 
Bevacizumab 15 mg/kg IV 
every 21 days 
 
 
 
 
 
 
 
 
 
 
 
*Patients whose creatinine clearance is ≥ 50 and < 60 mL/min will receive a divided dose, see 
Section 8.3 below. 
8.1 
Duration of treatment 
Treatment with gemcitabine and cisplatin should continue for a maximum of 6 cycles. 
Treatment with bevacizumab/placebo alone will continue as maintenance therapy until disease 
progression or unacceptable toxicity. Gemcitabine, cisplatin, and bevacizumab need not be 
given in the order listed below. 
8.2 
Gemcitabine 
1000 mg/m2 IV on Days 1 and 8, every 21 days.  
8.3 
Cisplatin 
Patients whose creatinine clearance is ≥ 60 mL/min will receive cisplatin at a dose of 70 
mg/m2 IV per institutional guidelines on Day 1 every 21 days. At least 1 liter of normal saline 
will be given intravenously for hydration prior to cisplatin. Patients may receive additional 
intravenous hydration, mannitol, electrolytes, or furosemide according to institutional practice. 


CALGB 90601 
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27 
At the beginning of any cycle, patients whose creatinine clearance is ≥ 50 and < 60 mL/min 
will be treated with cisplatin 35 mg/m2 on Day 1 and with cisplatin 35 mg/m2 on Day 8 of the 
cycle. At least 1 liter of normal saline will be given intravenously for hydration prior to 
cisplatin. Patients may receive additional intravenous hydration, mannitol, electrolytes, or 
furosemide according to institutional practice.  
If at the beginning of a subsequent cycle, creatinine clearance recovers to ≥ 60 mL/min, 
patients may resume full dose cisplatin on Day 1 of the cycle (with any applicable dose 
modifications per Section 9.0). 
8.4 
Bevacizumab/Placebo 
Bevacizumab/placebo 15 mg/kg IV is to be administered every 21 days. The initial dose is to 
be given over 90 minutes, second dose over 60 minutes, and all subsequent doses over 30 
minutes if prior infusions are tolerated without infusion-associated adverse events. 
See Section 9.13 for instructions regarding patients who require surgery. 
8.5 
Cisplatin-induced emesis 
For prophylaxis of cisplatin-induced emesis, a 5-HT3 antagonist and a corticosteroid are 
recommended. NK1 receptor antagonists such as aprepitant are allowed per institutional 
practices.  
8.6 
Aspirin  
81 mg daily p.o. should be considered at the discretion of the treating physician for all patients 
who are not already receiving daily aspirin and are at risk for arterial thromboembolic events 
(age ≥ 65, history of arterial thrombotic events). Aspirin should be considered because of the 
increased risk of arterial thromboembolic events from bevacizumab. Patients who cannot 
tolerate aspirin or in whom it is contraindicated should not receive it. 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
Skipped doses are not made up. If Day 1 treatment cannot be administered, initiation of all protocol 
treatment for that cycle should be delayed.  
Dose Levels for Gemcitabine 
Dose Level 
Gemcitabine 
Level 0 
1000 mg/m2 
Level -1 
750 mg/m2 
Level -2 
500 mg/m2 
Dose Levels for Cisplatin 
Dose Level 
Cisplatin 
CrCl ≥ 60 mL/min 
CrCl ≥ 50 and < 60 mL/min* 
Level 0 
70 mg/m2 
35 mg/m2 on Day 1, and 
35 mg/m2 on Day 8 of cycle 
Level -1 
50 mg/m2 
25 mg/m2 on Day 1, and 
25 mg/m2 on Day 8 of cycle 
Level -2 
36 mg/m2 
18 mg/m2 on Day 1, and 
18 mg/m2 on Day 8 of cycle 


CALGB 90601 
Version Date: 11/29/2018 
Update #12 
28 
Gemcitabine and cisplatin doses may be modified separately based on individual toxicity 
according to the rules outlined below. There is no dose reduction below level -2 for gemcitabine or 
cisplatin. If dose reduction below level -2 is required, gemcitabine and/or cisplatin should be 
discontinued. 
* Divided dose cisplatin: If at the beginning of any cycle, a patient’s measured or calculated 
creatinine clearance is ≥ 50 mL/min and < 60 mL/min, administer cisplatin at the appropriate 
dose level, but at a divided dose to be given on Days 1 and 8 of the cycle. 
Bevacizumab/placebo dose is always 15 mg/kg. Bevacizumab/placebo may be skipped or 
discontinued as described below, but the dose is not reduced. If 2 sequential doses of 
bevacizumab/placebo are skipped due to toxicity, bevacizumab/placebo should be permanently 
discontinued. If bevacizumab/placebo is discontinued, gemcitabine and cisplatin should be 
continued for a total of up to 6 cycles, or until disease progression or unacceptable toxicity. 
9.1 
Hematologic Toxicity 
9.1.1 
Gemcitabine and cisplatin dose guidelines for Day 1 hematologic toxicity 
For ANC < 1500 or platelets < 100,000 on Day 1, delay all protocol treatment, including 
bevacizumab/placebo, and repeat CBC weekly. Resume treatment with ANC improves to 
≥ 1500 and platelets improve to ≥ 100,000. 
• 
If treatment was delayed for 1 week, resume treatment at the previous doses of 
gemcitabine and cisplatin. 
• 
If treatment was delayed for more than one week and less than six weeks, reduce 
gemcitabine and cisplatin by one dose level for this and all subsequent cycles. 
For delays of 6 weeks or greater, discontinue gemcitabine and cisplatin. If gemcitabine 
and 
cisplatin 
are 
discontinued 
for 
hematologic 
toxicity, 
treatment 
with 
bevacizumab/placebo should be continued until disease progression or unacceptable 
toxicity. 
9.1.2 
Dose modifications for Day 8 hematologic toxicity 
For ANC 500-999 or platelets 50,000-74,999, decrease gemcitabine by one dose level for 
this and all subsequent doses. For patients receiving split dose cisplatin during this cycle, 
also decrease cisplatin by one dose level for this and all subsequent doses. 
For ANC < 500 or platelets < 50,000, skip gemcitabine and decrease gemcitabine by one 
dose level for all subsequent doses. For patients on split dose cisplatin during this cycle, 
also skip cisplatin and decrease cisplatin by one dose level for this and all subsequent 
doses. 
9.1.3  Dose modifications for hematologic toxicity outside of Day 1 and/or Day 8 
For patients with platelets < 50,000 with clinically significant bleeding (grade 2 or 
greater) at any time, dose reduce gemcitabine one dose level for next and all subsequent 
doses. 
9.1.4 
Febrile neutropenia: For febrile neutropenia (defined as temperature ³ 38.5° C [101° F] 
sustained for more than one hour concomitant with ANC < 500/mm3), reduce 
gemcitabine and cisplatin by one dose level for this and subsequent cycles.  


CALGB 90601 
Version Date: 11/29/2018 
Update #12 
29 
9.1.5 
Dose modifications during bevacizumab/placebo maintenance therapy 
For ANC < 500 or platelets < 25,000, hold bevacizumab/placebo treatment. Resume 
treatment when ANC improves to ≥ 1500 and platelets improve to ≥ 100,000. If treatment 
is held greater than 6 weeks for hematologic toxicity, discontinue bevacizumab/placebo. 
9.2 
Hepatic Dysfunction 
9.2.1 
For bilirubin > 1.5 x ULN (or > 3 x ULN for patients with Gilbert’s syndrome), delay 
treatment until bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert’s syndrome), 
then resume with one dose level reduction of gemcitabine and at the previous dose of 
cisplatin and bevacizumab. 
9.2.2 
If bilirubin > 1.5 x ULN despite two gemcitabine dose reductions, gemcitabine should 
be discontinued but cisplatin and bevacizumab/placebo may be continued. For patients 
with Gilbert's syndrome, if bilirubin > 3 x ULN despite two gemcitabine dose reductions, 
gemcitabine and cisplatin should be discontinued; treatment with bevacizumab/placebo 
may be continued. 
9.3 
Neurotoxicity  
9.3.1 
For grade 3 sensory or motor neuropathy, skip cisplatin until the toxicity resolves to ≤ 
grade 2 and then resume therapy with one dose level reduction of cisplatin on Day 1 of 
the next scheduled cycle. If cisplatin is skipped for two consecutive cycles, discontinue 
cisplatin. Treatment with gemcitabine and bevacizumab/placebo may continue. 
9.3.2 
For grade 4 sensory or motor neuropathy, skip all therapy until resolution to ≤ grade 
2, discontinue cisplatin; resume gemcitabine and bevacizumab/placebo at the previous 
dose. 
9.4 
Dose modifications for gastrointestinal toxicity 
For grade 3 or 4 nausea or vomiting despite maximal antiemetic therapy (including 5HT-3 
antagonist, corticosteroids, and aprepitant), discontinue cisplatin. Continue gemcitabine and 
bevacizumab/placebo at the previous dose when symptoms resolve to ≤ grade 1.  
9.5 
Dose modifications for Day 1 and Day 8 kidney function 
9.5.1 
For creatinine clearance < 50 mL/min (measured or calculated) on Day 1 of a cycle, 
delay all treatment until creatinine clearance improves to ≥ 50 mL/min. 
• 
If creatinine clearance improves to ³ 60 mL/min within 1 week, resume with one 
dose level reduction for cisplatin for all subsequent doses, and the previous dose of 
gemcitabine and bevacizumab/placebo.  
• 
If creatinine clearance improves to ³ 50 and < 60 mL/min within 1 week, resume 
with one dose level reduction of cisplatin for this and all subsequent cycles. 
Administer cisplatin as a split dose on Days 1 and 8 of this cycle. Resume 
gemcitabine and bevacizumab/placebo at the previous dose. 
• 
If creatinine clearance does not improve to ³ 50 mL/min within 1 week, skip cisplatin 
for this cycle only. Treat with gemcitabine and bevacizumab/placebo at the previous 
dose. For the next cycle, if creatinine clearance is still < 50 mL/min, discontinue 
cisplatin. Continue gemcitabine and bevacizumab/placebo. 


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9.5.2 
For creatinine clearance < 50 mL/min (measured or calculated) on Day 8 of a cycle, 
skip cisplatin for this day (applies only if split-dose cisplatin is indicated for this cycle). 
Refer to the above dose modifications for Day 1 dosing for the next cycle. 
9.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7 
 
 
 
 
 
 
 
 
 
 
 
9.8 
  
 
 
 
 
 
 
 
 
 
 
 
 
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9.8.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
9.10 
 
 
 
 
 
 
 
 
 
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9.11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.12 
Hypersensitivity and infusion reactions 
Note that the NCI CTCAE defines hypersensitivity reactions differently from infusion 
reactions: “Cytokine release syndromes/acute infusion reactions are different from 
allergic/hypersensitivity reactions, although some of the manifestations are common to both 
AEs. An acute infusion reaction may occur with an agent that causes cytokine release (e.g., 
monoclonal antibodies or other biological agents). Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of completion 
of infusion.” See the “Syndromes” section of the CTCAE version 3 for a complete list of signs 
and symptoms of “Cytokine release syndrome/acute infusion reaction;” and see the 
“Allergy/Immunology” section for a description of hypersensitivity. Note: Serious adverse 
events will be reported through CTEP-AERS using CTCAE version 5.0. 
9.12.1 Dose modifications for hypersensitivity reactions (for all agents) 
• 
For grade 1 hypersensitivity reactions (transient rash, drug fever < 38°C): 
Decrease the infusion rate by 50% until symptoms resolve, then resume at the initial 
planned rate. 
• 
For grade 2 hypersensitivity reactions (urticaria, drug fever ³ 38°C and/or 
asymptomatic bronchospasm): Stop infusion. Administer H1 and/or H2 blockers, 
and/or steroids according to institutional policy. Restart the infusion when symptoms 
resolve and pretreat before all subsequent doses. Treat according to institutional 
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• 
For grade 3 or grade 4 hypersensitivity reactions: Stop the infusion. Discontinue 
all protocol treatment and notify the study chair. 
9.12.2 Bevacizumab/placebo dose modifications for infusion reactions 
The initial bevacizumab/placebo dose should be administered over a minimum of 90 
minutes. If no adverse reactions occur, the second dose should be administered over a 
minimum of 60 minutes. Again, if no adverse reactions occur, the third and subsequent 
doses should be administered over a minimum of 30 minutes. If infusion-related adverse 
reactions occur, subsequent infusions should be administered over the shortest period that 
is well-tolerated. Patients may receive premedication with diphenhydramine 25 to 50 mg 
intravenously or orally 30 minutes prior to bevacizumab/placebo if they have previously 
experienced mild infusion reactions. Acetaminophen premedication may also be used. 
9.13 
Surgery 
For patients who require surgery while on study, it is recommended that 
bevacizumab/placebo be discontinued for at least 60 days prior to surgery whenever 
possible. For minor surgery such as port placement at least seven days is needed between the 
insertion and treatment with bevacizumab/placebo. Re-initiation of protocol therapy should be 
discussed with the Alliance Study Chair. 
9.14 
Fatigue 
For persistent fatigue interfering with activities of daily living (grade 2/3) during treatment 
with gemcitabine, cisplatin, and bevacizumab/placebo, any or all of these agents may be held 
for up to 3 weeks at the discretion of the treating physician.  
For persistent fatigue interfering with activities of daily living (grade 2/3) during treatment 
bevacizumab/placebo alone, bevacizumab/placebo may be held for up to 6 weeks at the 
discretion of the treating physician. 
9.15 
Other non-hematologic toxicities 
For all other treatment-related ≥ grade 3 non-hematologic toxicities not described above, hold 
all protocol treatment and monitor toxicity at least weekly. If toxicity resolves to ≤ grade 1 
within 6 weeks, treatment may be resumed, with gemcitabine and cisplatin at one lower dose 
level, and with bevacizumab/placebo at the previous dose. 
9.16 
Dose Modification for Obese Patients  
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely 
by the patient’s actual weight without any modification unless explicitly described in the 
protocol. This will eliminate the risk of calculation error and the possible introduction of 
variability in dose administration. Failure to use actual body weight in the calculation of 
drug dosages will be considered a major protocol deviation. Physicians who are 
uncomfortable with administering chemotherapy dose based on actual body weight should not 
enroll obese patients on Alliance protocols.  
10.0 CORRELATIVE SCIENCE SUBSTUDIES 
There are four components of the correlative science substudies for CALGB 90601 and all patients 
are encouraged to participate. The first part is comprised of serum-based biomarker studies and is 
described in Section 10.1. The second part is comprised of tissue-based biomarker studies and is 
described in Section 10.2. The third part is comprised of an evaluation of the effect of tobacco on 
bladder cancer outcomes. Taken together, these three sections make up the companion study 


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150609. The fourth part, pharmacogenomic studies in patients with advanced transitional cell 
cancer, is described in Section 10.4 and makes up the companion study, 60707.  
10.1 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
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C. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.2 Primary objective: 
To determine if serum-based biomarkers reflecting tumor angiogenesis are prognostic 
biomarkers of overall survival for patients with advanced transitional cell carcinoma 
receiving gemcitabine/cisplatin/bevacizumab or gemcitabine and cisplatin. 
Secondary objectives: 
1) To determine if patients with advanced TCC and elevated baseline levels of VEGF 
will have worse prognoses than patients with low baseline VEGF levels.  
2) To determine if elevated baseline levels of VEGF will predict for better response to 
bevacizumab/cisplatin/gemcitabine in patients with advanced TCC. Additionally, to 
determine if elevated levels of urinary VEGF and/or soluble plasma VEGFR2 on 
treatment will correlate with resistance to therapy and disease progression in patients 
with advanced TCC treated with bevacizumab/ cisplatin/gemcitabine. 
3) To determine if levels of non-VEGF angiogenic factors at baseline and during 
treatment will correlate with primary and acquired resistance to bevacizumab, 
respectively. 
4) To determine if proteomic profiling will help define novel markers of disease biology 
and can help predict for response to bevacizumab. 
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10.1.3 ELISA and coagulation assay methods 
Both EDTA and citrated plasma samples are required to meet the assay specifications for 
the various biomarkers. EDTA plasma will be collected in a standard 13 x 75 mm (5 mL 
purple top) tube. Three 5 mL EDTA tubes of blood should yield approximately 9 mL 
plasma after processing per time point. One 5 mL tube of citrated plasma will be 
collected for coagulation profiling. One 5 mL tube of serum (red top or SST) will be 
collected for proteomic profiling. One additional 5 mL tube of citrated plasma and one 
additional 5 mL tube of serum will be archived for further potential exploratory analyses 
related to predicting efficacy or toxicity of gemcitabine and bevacizumab or a better 
understanding of transitional cell cancer biology. In total, nine tubes of blood (40.8 mL) 
will be drawn at the time of registration, prior to Cycle 4, at the time of discontinuation of 
protocol therapy, and at progression (3 x 6 mL EDTA plasma, 4 x 2.7 mL citrate plasma, 
and 2 x 6 mL serum).  
Samples will be analyzed at Duke University using either SearchLight technology, 
commercially available ELISA assays (R&D Systems, Biosource), or ELISAs developed 
within our laboratory. Analysis of cytokine levels in urine will be normalized to 
creatinine.  
The CV’s of the ELISAs are typically 20% or less with sensitivities in the picogram 
range and a 3-4 log dynamic range. The CV’s of the multiplex arrays are approximately 
20%, depending on the particular assay. In order to validate each specific plate design, 
we will run samples spiked with known quantities of purified growth factors in parallel 
with study samples to verify the performance characteristics of the assays. Known 
amounts of cytokines will be added into buffer. The mean recovery for each cytokine will 
be ascertained. Any study samples that fall outside the linear portion of the standard 
curve will be retested. Samples that read below the limit of detection will be retested as 
neat plasma to confirm the initial results. Samples that read above the linear portion of 
the standard curve will be serially diluted and retested to obtain accurate measurements. 
Any analyte that does not meet the aforementioned criteria will result in the sample being 
re-evaluated.  
Thrombin/AT complexes, serum albumin, serum LDH, and urine creatinine 
determinations will be performed by the clinical laboratories at Duke University Medical 
Center.  
10.2 
Tissue-based chemotherapy resistance biomarkers 
10.2.1 Background 
Chemotherapy resistance continues to be a significant cause of morbidity and mortality in 
advanced bladder cancer. While many mechanisms of resistance have been suggested, 
there are no validated markers predictive for response to chemotherapy. However, 
biomarkers reflecting DNA repair mechanisms have now been found to have predictive 
significance for patient outcome following adjuvant cisplatin-based therapy for resected 
lung cancer 133 and functional resistance to cisplatin can also be achieved through re-
establishing effective homologous recombination to repair double-strand break (DSB).134, 
135 In this large, multi-institutional study, we propose to determine the predictive strength 
of markers of DNA repair mechanisms for patients with advanced transitional cell 
carcinoma treated with gemcitabine/cisplatin or gemcitabine/cisplatin/ bevacizumab.  
There is a significant literature focused on molecular determinants of chemotherapy 
sensitivity (primarily cisplatin and gemcitabine) in bladder cancer. Cisplatin resistance in 


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bladder cancer has been linked to multiple molecular features including altered 
expression of bcl-2,136, 137 p53,138 p73,139 inositol 1,4,5-trisphosphate receptor type 1140 to 
name a few of the most common. In contrast, p-Glycoprotein has generally been found to 
have low expression and transporters are thought to play less of a role.141 However, as yet 
no mechanism based biomarker has had sufficient predictive strength to warrant clinical 
use. 
Increasing evidence suggests that the status of DNA repair mechanisms, specifically 
nucleotide excision repair (NER) and homologous recombination (HR), impact a cancer 
cell’s sensitivity to agents causing interstrand cross links, DNA adducts, and double-
stranded breaks (DSB). For cisplatin based therapy, low levels of protein expression of 
excision repair cross complementation 1 (ERCC1) have been associated with improved 
survival following adjuvant therapy in lung cancer.133 In patients with advanced lung 
cancer treated with the combination of gemcitabine and cisplatin, low expression of both 
excision repair cross complementation 1 (ERCC1) and ribonucleotide reductase M1 
(RRM1) were both found to be associated with median survival time.142 In addition, two 
papers have recently demonstrated that the status of BRCA2, which plays a functional 
role in homologous recombination, is important to sensitivity to cisplatin and PARP.134, 
135 Specifically, BRCA2 -/- (BRCA2 null and, as a result, HR deficient) ovarian cell lines 
and cultured tumor cells selected for resistance to PARP and cisplatin treatment were 
found to genetically restore BRCA2 function and restore HR. A potential biomarker for 
intact HR is nuclear Rad51 staining, as immunofluorescent detection of Rad51-
containing foci in the nuclei of cells suggests intact HR.143 Thus, there is strong evidence 
that a tumor’s ability to repair interstrand cross links through NER and HR may strongly 
impact overall tumor sensitivity to cisplatin-based therapy and biomarkers for DNA 
repair mechanisms may anticipate clinical response to therapy. 
Preliminary investigations in bladder cancer suggest that DNA repair mechanisms may 
impact clinical response to chemotherapy. With respect to DNA repair mechanisms, 
hMLH-1 and hMLH-2 have been found to have high expression in bladder cancer.139 In 
advanced bladder cancer, low mRNA expression of ERCC1 has already been found to be 
associated with improved survival (25.4 mo v. 15.4 m, P=0.03) in a small number of 
patients treated with chemotherapy (n = 57) 144 and other mRNA levels of other DNA 
repair genes such as RRM1, BRCA1, and caveolin-1 had a trend toward significance but 
did not meet statistical threshold in this small study.144 
Importantly, while the interaction between cisplatin and DNA repair mechanisms may be 
the primary biology driving clinical benefit from the combination of gemcitabine and 
cisplatin, expression of a few of the same proteins have been associated with gemcitabine 
response. RRM1 overexpression has been associated with resistance to gemcitabine 145 
and caveolin-1 expression is also associated with poor outcomes with gemcitabine-based 
chemotherapy.146 
Here, formalin-fixed paraffin embedded primary tumors from patients enrolled on 
CALGB 90601 will be requested and stored at the Alliance Biorepository at OSU. Tissue 
microarrays will be created and biomarkers reflecting the status of DNA repair in these 
primary tumors will be assessed for their predictive strength when patients are treated 
with cisplatin/gemcitabine or cisplatin/ gemcitabine/bevacizumab. Specific markers to be 
assessed include ERCC1, Rad51, RRM1, BRCA1, BRCA2, and caveolin-1. Specifically, 
A) expression of ERCC1, Rad51, RRM1, BRCA1, BRCA2, and caveolin-1, B) 
immunofluorescence will be used to determine the nuclear pattern of Rad51, and C) 
germ-line polymorphisms in ERCC1 (118C/T and C8092A) will be assessed for their 
association with outcome in patients with advanced TCC. 


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The hypotheses of the tissue based analysis are: 
• 
Low levels of ERCC1 expression by immunohistochemistry are associated with 
improved progression free or overall survival. Building upon results from lung 
cancer and preliminary studies in bladder cancer, we will definitively determine if 
low ERCC1 levels, as measured by IHC, are associated with improved clinical 
outcome following cisplatin based therapy. Low ERCC1 levels suggest impaired 
nucleotide excision repair which is the first step in the repair of interstrand cross 
links. As this is the major mechanism by which cisplatin exerts its cytotoxic impact, 
poor DNA repair capability is likely to result in increased cellular apoptosis in 
response to cisplatin. While we will be determining ERCC1 levels in primary tumor 
blocks and treating metastatic disease, the compelling preliminary data from lung 
cancer establishing an association between low ERCC1 expression in primary lung 
cancers and finding a survival benefit following adjuvant chemotherapy, suggests 
that primary tumor expression of ERCC1 is relevant to metastatic disease. 
• 
Expression of alternative markers of DNA repair (Rad51, RRM1, BRCA1, 
BRCA2, and caveolin-1) are associated with improved progression free or 
overall survival. While ERCC1 is the most widely used and validated biomarker 
reflecting a cell’s capacity for DNA repair, variation in Rad51, RRMI, BRCA1, 
BRCA2, and caveolin-1 may also reflect DNA repair and provide prognostic or 
predictive biomarkers. Each of these markers have been found to be expressed in or 
associated with bladder cancer. Rad51 has variable expression across multiple 
bladder cancer cell lines 147 but its association with prognosis or response to 
chemotherapy remains unknown. RRM1 expression correlates with increased 
survival in patients with advanced bladder cancer.144 BRCA1 gene hypermethylated 
has been shown to help with diagnosis when detected in the urine sediment 148 and 
IHC for both BRCA1, BRCA2, and Rad51 has been shown to be predictive for 
response to radiation therapy in breast cancer.149 Finally, expression of Caveolin-1 
staining has been found to be present in bladder cancer tumors and correlates with 
tumor grade.150 These proteins will be assessed for expression and correlated with 
progression free survival and overall survival. 
• 
Nuclear Rad51 staining patterns by immunofluorescence is associated with 
progression free or overall survival. While expression level of Rad51 may provide 
sufficient information with respect to cisplatin sensitivity, the specific pattern of 
Rad51 expression in the nucleus is a more accurate marker of intact homologous 
recombination. Immunofluorescence for Rad51 performed on the TMA will be 
assessed and each tumor will be annotated for the presence or absence of Rad51-
containing nuclear foci. The progression free and overall survival of individuals with 
tumors having Rad51-containing nuclear foci present will be compared to those 
without the nuclear foci. 
10.2.2 Primary objective 
To determine if low levels of ERCC1 expression is prognostic of overall survival in 
patients with advanced transitional cell carcinoma treated with gemcitabine/cisplatin 
and/or gemcitabine/cisplatin/bevacizumab. 


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Secondary objectives 
1) To determine if low levels of ERCC1expression by immunohistochemistry is 
associated with improved progression free survival. 
2) To determine if expression of alternative markers of DNA repair (Rad51, RRM1, 
BRCA1, BRCA2, and caveolin-1) are associated with improved progression free or 
overall survival 
3) To determine if nuclear Rad51 staining patterns by immunofluorescence is associated 
with progression free or overall survival. 
10.2.3 Methods for Tissue Protein Analysis 
Outcome-linked paraffin-embedded tissues from patients on randomized treatment trials 
constitute a valuable but consumable resource for studies of tumor biology and treatment 
response. In order to make maximal use of the tissue resources provided by this study, 
tissue microarrays (TMAs) containing tumor from all participants who have their paraffin 
blocks sent to the Alliance Biorepository at Ohio State University will be constructed to 
facilitate targeted protein analysis using immunohistochemistry. TMAs will be 
constructed at the Alliance Biorepository at Ohio State University. Briefly, H&E stained 
slides will be reviewed, and areas marked from which the donor cores should be taken. In 
general, areas measuring at least 7 mm in diameter are preferred in order to facilitate the 
harvesting of at least 6 cores of tissue (3 in the primary TMA block and 3 in the 
duplicate). Arrays are constructed with 3 additional cores of normal corresponding tissue 
at one end for orientation. The TMA’s will be stored at the Alliance Biorepository at 
OSU and sent to investigators for the analysis of specific markers. These TMAs can be 
used for both immunohistochemistry and immunofluorescence. 
Biomarker immunostaining of the TMA’s will be performed using a Ventana automated 
immunostainer, which not only increases the rate at which novel immunohistochemistry 
and in situ hybridization markers can be optimized for staining TMAs, but also can match 
the staining methods used in large hospital diagnostic laboratories, facilitating translation 
of validated markers into clinical use for diagnosis or prediction. Image capture and 
scoring will be facilitated by automated digital imaging systems (Bacus Lab Inc Slide 
Scanner (BLISS)), which accelerates the rate at which biomarkers can be scored, 
provides a secure image archive linked to secure molecular and clinical database, permits 
on-line publication of results, and yields high quality images suitable for quantitative 
analyses. Cores will be visualized with a Web based image display at 20X magnification. 
To assist with diagnostic interpretation in NHT tissues, H&E and CK5/6 stained replicate 
array slides will be used. In untreated tissue cores, nuclear grade will be assigned to each 
specimen on the TMA. Subjective visual scoring and objective computer assisted scoring 
systems will be applied to each stained slide and an automated intranet analysis system 
that displays images, scoring results as well as clinical features of each patient will be 
used to facilitate analysis. 
Biomarker evaluation: The staining intensity of malignant tissue will be evaluated and 
scored by a minimum of two pathologists, as well as automated quantitative image 
analysis by pro-plus image software (MediaCybernetics, San Diego, Ca). For scoring of 
the majority of markers, including ERCC1, Rad51, RRM1, BRCA1, BRCA2, and 
caveolin-1, specimens will be graded from 0 to +3 intensity representing the range from 
no staining to heavy staining, as previously reported.133, 149-167 The overall percentage of 
cancer cells showing staining (0-100%) will also be reflected in the score as follows:  
0: 
No reactivity 
1+: 
Weak reactivity, with 0-10% of tumor cells showing positive staining. 


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2+:  Moderate activity, with 10-50% of tumor cells showing positive staining. 
3+:  Strong reactivity, with > 50% of tumor cells showing positive staining.  
Immunofluorescence of nuclear Rad51 will be performed on the TMAs as previously 
described 135 and scored as absent (0) or present (1). The presence of any Rad51-
containing nuclear foci suggests intact homologous recombination thus making this 
dichotomous grading appropriate. 
10.3 Evaluation of somatic mutations and copy number changes associated with 
treatment response 
10.3.1 Background 
Cisplatin-based combination chemotherapy represents standard therapy for patients with 
metastatic transitional cell carcinoma (1, 2). While response rates to chemotherapy are 
high in this disease, durable remissions remain rare, in only 9-20% of patients (3, 4). The 
lack of a predictive biomarker for benefit from cisplatin-based chemotherapy has limited 
the use of this relatively toxic approach in the urological community; only a minority of 
patients actually receives cisplatin chemotherapy.(5) Prospective identification of those 
patients most likely to benefit has not been possible, as no predictive biomarker has been 
identified. However, cisplatin-based therapy can be curative in those 9-20% of patients, 
and beyond clinical prognostic factors (6) there is no way to identify them in advance. 
Cisplatin administration leads to inter- and intra-strand DNA adducts, resulting in DNA 
cross-linkage and cell death. Cisplatin-induced DNA damage repair (DDR) occurs 
primarily through the nucleotide excision repair (NER) pathway(7), with additional repair 
via homologous recombination.(8) NER occurs initially through two sub-pathways 
(global repair and transcription-coupled repair), followed by downstream convergence in 
a common pathway. The NER pathway is comprised of multiple genes, including 
ERCC1-5. ERCC2 is a DNA helicase within the transcription factor IIH (TFIIH) 
complex that opens DNA around a damaged lesion to allow excision repair.(9) Many 
TFIIH genes are implicated in recessive inherited DDR disorders such as xeroderma 
pigmentosum (XP), Cockayne syndrome, and trichothiodystrophy. Whole exome 
sequencing (WES) of muscle invasive TCGA specimens identified recurrent somatic 
mutations in ERCC2 in 12% of tumors.(10) 
Multiple studies have implicated germline NER single nucleotide polymorphisms (SNPs) 
as modulators of cisplatin-based chemotherapeutic efficacy in cancer patients,(11, 12) 
although prospective assessment of either germline SNPs(13) or expression changes(14) 
in NER genes have not confirmed these findings. In vitro experiments have previously 
demonstrated that cell lines with deficiencies in the transcription-coupled NER sub-
pathway, including members of the TFIIH complex, have enhanced sensitivity to 
cisplatin.(15, 16) However, no previous work has rigorously evaluated the NER pathway 
for somatic alterations in tumors. 
Preliminary work has identified ERCC2 somatic mutations as predicting exquisite 
sensitivity 
to 
neoadjuvant 
cisplatin-based 
chemotherapy 
(MVAC 
or 
gemcitabine/cisplatin) in patients with muscle invasive transitional cell carcinoma.(17) 
Patients with pathological complete response (pT0 or pTis; n=25) vs. no-response or 
progression (n=25) in the cystectomy specimen underwent whole exome sequencing of 
DNA extracted from untreated transurethral resection specimens (complete responders) 
or post-treatment cystectomy with matched germline samples. ERCC2 missense 
mutations in 36% of patients with CRs (ERCC2 [XPD] n=9). Strikingly, none of the 
platinum-resistant tumors harbored these mutations. Since the somatic ERCC2 mutation 
prevalence in The Cancer Genome Atlas bladder cancer cohort was 12%, the mutation 


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frequency in CRs (35%) was dramatically higher than expected in unselected patients 
(q<0.001). Six of 9 ERCC2 mutations in cisplatin-sensitive patients lay within consensus 
helicase domains required for ERCC2 function. One additional mutation is adjacent to a 
helicase domain. The 3D structure of ERCC2 indicates that the extreme sensitivity 
mutations line the DNA interaction cleft; these regions are conserved from Archaea to 
humans suggesting a highly conserved function. 
While ERCC2 may be closely linked with response to cisplatin-based therapy, only a 
minority of responders possess these mutations. Somatic mutations in other DNA damage 
response genes have been reported to have an association with response to cisplatin-based 
therapy.(18) Whether these mutations impact overall survival is not clear. 
The association between other somatic mutations and survival in metastatic transitional 
cell carcinoma has not been fully elucidated in a large prospectively collected cohort. 
TCGA bladder cancer cohort remains immature, and many patients have not developed 
metastatic disease. Therefore, evaluating whether other somatic mutations are associated 
with good or poor outcomes in metastatic disease remains a relevant question.  
The availability of high-throughput next-generation sequencing platforms that are able to 
handle small quantities of DNA from formalin-fixed paraffin embedded tissues has 
allowed large-scale assessment of multiple genes at reasonable cost. IMPACT (Integrated 
Mutation Profiling of Actionable Cancer Targets) (19) is a 340 gene next-generation bait-
capture sequencing assay designed to capture and sequence all protein-coding exons and 
select introns of 300 cancer-associated genes to 500-1000x coverage, and includes 
ERCC2 plus other DNA repair genes. 
10.3.2 Rationale 
Based on these findings in muscle invasive patients, we hypothesize that somatic 
mutations in ERCC2 are associated with more durable responses in patients with 
metastatic transitional cell carcinoma treated with cisplatin-based chemotherapy.  
Conversely, we hypothesize that lack of an ERCC2 somatic mutation is associated with a 
lower likelihood of a durable response to chemotherapy. As patients on both arms of this 
trial are treated with gemcitabine and cisplatin chemotherapy, this patient population is 
ideal to test the hypothesis that ERCC2 somatic mutation is associated with enhanced 
clinical benefit to cisplatin-based combination therapy. While the magnitude of benefit 
associated with an ERCC2 mutation may differ between the bevacizumab and placebo 
arms, we hypothesize that ERCC2 mutations will predict improved survival in both arms. 
We will also determine the impact of ERCC2 mutation on objective response and 
progression-free survival. Finally, we will explore the role of other somatic mutations on 
overall survival. 
Recent data suggests that both immunotherapy (e.g. MPDL3280a)(20) and targeted 
agents (e.g. anti-FGFR3)(21) may find wider use in advanced UC. Predictors of response 
to these agents (e.g. PD-L1 immunohistochemistry, FGFR3 mutation and fusion) are 
being explored, and ultimately patients may be selected for therapy based on the presence 
of a molecular biomarker. Similarly, the emerging evidence cited above suggests that 
identification of patients who will derive maximum benefit from cisplatin-based 
chemotherapy will allow rational selection of patients for this potentially curative 
therapy. If somatic ERCC2 mutation predicts overall survival with cisplatin-based 
combination chemotherapy, then “standard” cisplatin-based therapy may become a 
biomarker-driven therapy, and patients who may not derive significant benefit may be 
directed towards other therapeutic approaches which appear to hold promise. 


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10.3.3 Objectives 
Primary objective 
Determine whether somatic ERCC2 mutation predicts overall survival in patients treated 
with cisplatin-based therapies. 
Secondary objectives 
Determine whether ERCC2 somatic mutation is a predictive biomarker of objective 
response and progression-free survival 
Exploratory objectives 
Determine whether somatic mutations in other cancer-related genes predict overall 
survival, progression-free survival, and objective response to cisplatin-based 
chemotherapy.  .    
10.3.4 Methods 
DNA will be extracted from both germline blood specimens and tumor blocks. IMPACT 
sequencing will be performed at MSKCC. Sequence reads will be aligned using the 
Burrows-Wheeler Aligner and post-processed using the Genome Analysis Toolkit 
following standard best practices.(22, 23) Variants, sequence coverage, and copy number 
alterations in tumor samples will be determined using additional algorithms developed at 
the Broad Institute.(23) Tumor and matching germline DNA are analyzed 
simultaneously. In over 1000 tumor-normal pairs, IMPACT has achieved >250x coverage 
of >98% of targeted exons. A further analysis performed in matched frozen and FFPE 
samples found a ≥ 97% concordance with no excess of false positives within FFPE 
material.(24) The exon capture approach requires as little as 15ng input DNA allowing 
analysis of metastatic fine needle and core biopsy specimens. High coverage depth allows 
mutant allele detection even in the setting of stromal admixture. Optimization ensures 
complete coverage of key genes compared to commercial whole exome capture. 
Currently, IMPACT gene list includes ERCC2 and many additional DNA-damage 
response genes. If superior sequencing technology is available at the time of analysis that 
provides similar or improved information, it may be substituted for IMPACT sequencing. 
10.3.5 Power Computation and Data Analysis 
The primary endpoint for this CS analysis is overall survival. It is expected that 80% of 
patients enrolled on this study to have germline and tumor DNA available. Based on 
muscle invasive bladder TCGA cohort, the prevalence of ERCC2 is expected to be 12%. 
Since this represents a metastatic cohort, it is not certain what the prevalence will be in 
this group of patients. The null hypothesis is that the hazard ratio=1 for survival. Table 1 
provides the detectable hazard ratio assuming a two-sided type I error rate of 0.05, power 
of 0.80, event rates of 0.89, and ERCC2 somatic mutation prevalence of 0.05-0.15. The 
power computations are based on the assumption that the OS endpoint follows an 
exponential distribution and 400 patients have available DNA. 
Table 1. Detectable hazard ratio under a range of conditions and assuming a two-sided 
type I error rate =0.05, and 0.80 power. 
 
Prevalence of  ERCC2  
somatic mutation 
Hazard Ratio 
0.05 
            1.98 


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In addition, power calculations are based on testing treatment by ERCC2 somatic 
mutation interaction is provided in Table 2. The null hypothesis is that there is no 
treatment-ECCR2 somatic mutation interaction. The hypothesized median OS time in the 
treatment trial are 13.8 and 18.68 months for the gemcitabine/cisplatin and the 
gemcitabine/cisplatin/bevacizumab arms, respectively. No discrepancy in OS distribution 
is expected for the gemcitabine and cisplatin arm (i.e the hazard rate =0.0502 in both the 
mutated and unmutated groups). It is assumed that the OS distribution follows an 
exponential distribution, an accrual rate of 400 patients over 36-months period, and 36 
months post-accrual follow-up. Adequate power will be detected for only large 
interaction terms. Table 2 presents the power for testing the null hypothesis of no 
treatment effect by ERCC2 somatic mutation interaction using a two-sided type I error 
rate  a = 0.05 and assuming ERCC2 prevalence of 0.12. Let ∆1 and ∆2 be the hazard 
ratios for treatment effect within ERCC2 mutated and wild-type patients, respectively.  
Table 2. 
Prevalence of ECCR2 
Mutation 
∆1 
∆2 
Power 
0.12 
1.0 
2.5 
0.81  
 
1.0 
2.4 
0.77 
 
1.0 
2.3 
0.73 
 
1.1 
2.5 
0.70 
 
1.1 
2.4 
0.67 
 
1.1 
2.2 
0.57 
10.3.6 Data Analysis: 
The proportional hazards (PH) model will be used for assessing the prognostic value of 
ERCC2 mutation in predicting PFS and OS adjusting for the stratification factors. 
Furthermore, the Kaplan-Meier method will be used to estimate PFS and OS by ERCC2 
mutation status. In addition, the PH model will be used to assess the predictive 
importance of ERCC2 status in predicting PFS and OS adjusting on treatment arm, 
ECCR2 status and treatment-ERCC2 interaction with and without the stratification 
factors. The chi-square test will be used to compare the two mutations groups by the 
complete response status. The Logistic regression model will be utilized to assess the 
prognostic important of the ERCC2 mutation in predicting the probability of having a 
complete response, adjusting for treatment arm, and stratification factors. Estimates of the 
hazards ratios for PFS and OS or Odds Ratio of CR will be presented separately within 
each treatment arm if there is a suggestion that there is an ERCC2 mutation-treatment 
arm interaction.  
Additionally, IMPACT will identify co-mutation patterns in metastatic UC, as the 
genotype of metastatic urothelial carcinoma has not been thoroughly investigated. Their 
impact on outcomes (OS, ORR, PFS) will be evaluated as above purely in an exploratory 
hypothesis generating fashion. Finally, additional genes beyond those in the IMPACT 
0.10 
 1.64 
0.12 
1.58 
0.15 
1.52 


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panel may be tested if new genes are identified that may be relevant to urothelial 
carcinoma biology by spiking in a customized bait panel. 
10.4 
Pharmacogenomic companion study 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.5 
Evaluation of the Relationship between Intrinsic Subtype Membership and Treatment 
Response 
10.5.1 Background 
Bladder cancers are clinically heterogeneous with different patterns of progression and 
response to conventional and targeted therapies.  Several recent, large-scale genomics 
projects were completed that provided new insight into potential molecular mechanisms 
that control this heterogeneity. Whole genome mRNA expression profiling revealed that 
muscle invasive bladder cancers (MIBCs) can be grouped into intrinsic basal and luminal 
subtypes that share similarities with the corresponding subtypes of breast cancer and 
display distinct clinical characteristics (201-204).  Like their breast cancer counterparts, 
basal MIBCs were intrinsically aggressive – they were enriched with epithelial-to-
mesenchymal (EMT) and stem cell biomarkers and were associated with advanced stage 
and metastatic disease at presentation and shorter disease-specific and overall survival in 
the absence of chemotherapy.  However, a subset of basal MIBCs, characterized by 
enrichment with a gene expression signature indicative of T and B cell infiltration, were 
sensitive to neoadjuvant cisplatin-based combination chemotherapy (NAC) (202), and as 
a consequence, NAC produced the greatest clinical benefit in patients with basal tumors 
(205).  Conversely, tumors that belonged to the “p53-like” luminal MIBC intrinsic 
subtype were resistant to NAC (202,205). These observations are consistent with parallel 
studies in breast cancer, where NAC produced the largest impact in patients with basal-
like cancers and much less (if any) benefit in patients with luminal A cancers (206).  
The gene expression patterns that characterize the intrinsic basal and luminal MIBC 
subtypes contain features that suggest that they will be sensitive to distinct panels of 
targeted agents (207).  In addition to being enriched with immune checkpoint biomarkers, 
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basal MIBCs contain an active HIF-1a gene expression signature (202) and micro RNAs 
that are known to be direct targets of HIF-1 (A. Ochoa et al, manuscript under review). 
Therefore, it is possible that HIF-1 pathway-targeting agents, including inhibitors of 
vascular endothelial growth factor (VEGF) or its receptors, will have clinical activity in 
basal MIBCs. Consistent with this idea, patients with basal tumors who were enrolled in a 
recently completed Phase II clinical trial of dose-dense MVAC (DDMVAC) plus 
bevacizumab (Avastin) had unusually good clinical outcomes when compared with 
patients with basal tumors who were treated with neoadjuvant DDMVAC alone (205). 
The MD Anderson SPORE in Bladder Cancer has established a Genomics Core, located 
in the Department of Urology, and led by Woonyoung Choi, PhD.  The Core’s priority 
has been to develop methods for generating high quality mRNA expression profiling data 
from archival FFPE tissues, focusing on macrodissected material from unstained slides.  
The Core has performed quality control experiments on two new RNAseq platforms 
(Illumina’s TrueSeq RNA Access and Ion Torrent’s Ampliseq) and has concluded that 
they both generate very high quality data.  However, the Ampliseq platform requires less 
RNA (10 ng versus 20-100 ng for TrueSeq) and can produce high quality data from RNA 
that would fail the Illumina quality control standards (i.e., less than 30% of the RNA 
fragments are greater than 200 bp in length).   
10.5.2 Rationale 
Basal bladder cancers are enriched with an active HIF-1 gene expression signature, and 
patients with basal tumors had the best clinical outcomes in a completed Phase II clinical 
trial of DDMVAC plus Avastin.  Therefore, we predict that therapy with GC plus Avastin 
produced more clinical benefit in the patients enrolled in Alliance 90601 whose tumors 
belonged to the basal intrinsic subtype than it did in patients with luminal tumors or in 
patients with basal tumors treated with GC alone.  Conversely, we predict that the 
patients whose tumors belonged to the p53-like subtype had the worst clinical outcomes 
in both arms of the trial because of intrinsic chemoresistance and absence of the HIF-1 
gene signature.  Finally, we predict that tumor intrinsic subtype membership will 
correlate with the presence of specific DNA alterations identified in 10.3, consistent with 
previous studies in other tumor cohorts.   
10.5.3 Primary objective 
To determine whether patients with p53-like luminal tumors had the worst clinical 
outcomes (i.e., shorter PFS and/or OS). 
10.5.4 Secondary objectives 
To determine whether combination therapy with GC plus Avastin produced the most 
clinical benefit (i.e., longer PFS and/or OS) in patients with basal bladder cancers. 
To determine whether patients treated with GC alone whose basal tumors contained an 
immune infiltration signature had better outcomes than did patients whose basal 
tumors did not. 
To correlate intrinsic subtype membership with the presence of mutations and CNVs 
associated with chemo-sensitivity and/or resistance (in conjunction with 10.3) 
To correlate intrinsic subtype membership with the presence of mutations and CNVs (i.e., 
in RB1, FGFR3, PPARG, RXR, FOXA1, GATA3, etc) that were enriched in basal or 
luminal tumors in previous studies 


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10.5.5 Methods 
Ion Torrent’s Ampliseq platform will be used to generate whole transcriptome RNA 
expression data from all available tumors.  Total RNA will be purified from 
macrodissected 10 µm unstained slides (5 slides) using Roche HiPure FFPE miRNA 
Isolation kits (using the total RNA isolation method and a marked H&E-stained slide as a 
template. RNA purity and integrity will be measured using a Nanodrop instrument 
(Thermo Fisher) and a Bioanalyzer (Agilent Technologies, Inc), and the fraction of RNA 
fragments that are greater than 200 bp in length will be quantified. Ten nanograms of 
total RNA will be used for library and template preparation according to the 
manufacturer’s instructions (Ion Torrent, Thermo Fisher) and will be sequenced on an 
Ion Proton sequencer.   Normalized read count data will be generated using the AmpliSeq 
RNA plug-in in the Torrent Suite software package that is provided with the Ion Proton 
sequencer.  These data will be used to assign the tumors to intrinsic subtypes using a one 
nearest neighbor (oneNN) classifier developed by Woonyoung Choi (202).  Subtype 
assignments will be compared to those generated using an independent classifier 
(BASE47) developed by William Kim, MD, PhD (University of North Carolina).  The 
RNAseq data will be uploaded to GEO and released to the public once the manuscript 
describing the results is has been accepted for publication.  Residual total RNA will be 
returned to the Alliance tissue bank.  Notably, changes to the methods for any of the 
above procedures may be adapted depending upon the most recent, generally accepted 
protocols. 
Power Computation and Data Analysis 
It is hypothesized that p-53 like basal bladder cancers have worst prognosis than patients 
without the basal signatures. The primary goal for this correlative science component is 
to test whether p-53 like subtype bladder patients have a worse prognosis than non-basal 
subtype. The primary endpoint for this analysis is overall survival. It is assumed that 33% 
(n=67) of the patients are expected to have p-53-like tumors and 67.7% of the patients 
would have either basal or luminal tumors. There are 200 patients with tumor specimen 
available and it is expected that 89% (178 events) of the patients would experience an 
event. With 178 deaths, the log-rank test has 80% power to detect a hazard ratio of 1.56 
assuming a two-sided type I error rate of 0.05 and that OS follows an exponential 
distribution. 
Data Analysis 
The log-rank statistic will be used to test if the p-53 like tumors have worst OS compared 
to the non-basal tumors. In addition, the proportional hazards (PH) model will be used to 
estimate the treatment effect of bevacizumab in p53-like tumors, luminal and basal 
tumors. Furthermore, the Kaplan-Meier method will be used to estimate PFS and OS by 
the three subtypes. Finally, in an exploratory data the proportional hazards (PH) model 
will be used for testing for the intrinsic subtype (p53-like, luminal, basal) treatment arm 
interaction terms in models of PFS and OS 
Finally, the data will be used to validate the classifiers that assign subtype developed by 
Choi (202), BASE47 developed by Damrauer (University of North Carolina) (203).  
 


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11.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves 
and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment.  
Discard unused portions of injectable chemotherapeutic agents that do not contain a bacteriostatic 
agent or are prepared with un preserved diluents (i.e., Sterile Water for Injection USP or 0.9% 
Sodium Chloride for Injection USP) within eight hours of vial entry to minimize the risk of 
bacterial contamination. 
The total administered dose of study drug may be rounded up or down within a range of 5% of the 
actual calculated dose. Drug dosages need not be changed unless the calculated dose changes by at 
least 10%. 
11.1 
Gemcitabine (2’deoxy-2’,2’-difluorocytidine; dFDC; difluorodeoxycytidine; gemcitabine 
hydrochloride; Gemzar®)  
Please refer to the FDA-approved package insert for gemcitabine for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.  
Gemcitabine is a nucleoside analogue in the pyrimidine antimetabolite class which is S-phase 
specific. Its phosphorylated product is incorporated into DNA and interferes with DNA 
synthesis. Gemcitabine also exhibits self-potentiation by causing an enzymatically-mediated 
reduction in the intracellular nucleotide pool. 
Availability 
Gemcitabine is commercially supplied as a powder for reconstitution in 200 and 1 gram vials. 
Storage and Stability 
Intact vials containing sterile powder are stored at room temperature. When prepared as 
directed, reconstituted vials are reportedly stable for 35 days at room temperature and 
protected from light. Further diluted solutions of gemcitabine are stable for up to 7 days at 
room temperature when protected from light. However, the manufacturer recommends that 
solutions be used within 24 hours. The diluted solution should be clear and colorless to light 
straw-colored solution. 
Preparation 
Reconstitute the 200 mg vial with 5 mL 0.9% NaCl and the 1 g vial with 25 mL 0.9% NaCl. 
The resulting solution is approximately 38 mg/mL, but the concentration varies. It is suggested 
that when the desired dose is less than the entire vial, the entire volume be drawn up into a 
syringe in order to determine the actual concentration. Then the desired amount should be 
measured and diluted in 0.9% NaCl for infusion. 
Administration 
In this study, gemcitabine will be given intravenously over 30 minutes in an appropriate 
volume of 0.9% NaCl.  
Toxicities 
Common toxicities include a flu-like syndrome manifested by fever, fatigue, myalgias, 
headache, and cough. Myelosuppression is the usual dose limiting toxicity. Infusions longer 
than 1 hour as planned in this study are associated with increased myelosuppression. Mild 
elevations in hepatic transaminase levels occur in as many as two-thirds of patients but are 
reversible. Dyspnea occurs in 10-23% and is occasionally associated with a drug-induced 
pneumonitis. More often, dyspnea is likely associated with the underlying malignancy. 
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stomatitis and diarrhea or constipation occur less often. Proteinuria and hematuria are usually 
asymptomatic though frequent. A serious hemolytic-uremic syndrome is, however, rare (<1%). 
Paresthesias and peripheral neuropathies occur in 2-10%. Allergic reactions including 
bronchospasm occur infrequently (4%). Minimal alopecia (15%) and macular or 
maculaopapular rashes have also been reported.  
11.2 
Cisplatin 
Please refer to the FDA-approved package insert for cisplatin for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.  
Cisplatin is a platinum-containing heavy metal complex which acts as an alkylating agent. 
Cisplatin inhibits DNA synthesis by the formation of interstrand and intra-strand DNA 
crosslinkages, denaturation of the DNA double helix, and covalent binding to DNA bases.  
Availability 
Cisplatin is commercially available as a 1 mg/mL concentration aqueous injection in multidose 
vials of 50 mL, 100 mL, and 200 mL.  
Storage and stability 
Intact vials should be stored at room temperature and be protected from light. Solutions diluted 
in 0.9% or 0.45% NaCl to a concentration of 0.05-2mg/mL are stable for up to 72 hours at 
room temperature and protected from light.  
Administration 
Cisplatin is to be administered as an intravenous infusion according to institutional practice. 
Patients should receive intravenous hydration with at least 1 L of NaCl prior to cisplatin. 
Needles, syringes, catheters, or IV administration sets containing aluminum parts should not 
be used, as contact with cisplatin yields a black precipitate. 
Toxicity 
Common toxicities (> 10%) include nausea and vomiting which can occur within 24 hours 
and/or may be delayed up to 1 week following cisplatin, and are almost universal in the 
absence of effective antiemetic agents. Renal impairment is also not uncommon, but can be 
minimized with aggressive hydration. In addition to increases in BUN and creatinine, renal 
tubular damage leads to renal sodium, water, magnesium and potassium wasting, causing 
hypovolemia, hypomagnesemia and hypokalemia. Nephrotoxicity is worse in the presence of 
an obstructed urinary tract. Ototoxicity occurs in 10-30% and mainly consists of high 
frequency hearing loss (above the range of speech tones), which is largely irreversible. 
Neurotoxicity is a dose- and duration-dependent axonal degenerative process which is 
clinically manifested as irreversible peripheral neuropathy. Leukopenia and thrombocytopenia 
are mild and typically reverse in 3 weeks. A slowly progressive anemia is often noted with 
continued cisplatin therapy. Rarely, an anaphylactic reaction can be seen within a few minutes 
of administering cisplatin. Other rare toxicities (<1%) include mild alopecia, local phlebitis at 
the injection site, arrhythmias, optic neuritis and papilledema. 
11.3 
 
 
 
 
 
 
 
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12.0 ANCILLARY THERAPY 
12.1 
Supportive care 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, dosage, 
and the dates of treatment should be recorded on the CALGB Remarks Addenda (C-260). 
12.2 
Palliative radiation 
Palliative radiation therapy may not be administered while the patient is on study treatment. A 
symptomatic lesion or one which may produce disability (e.g., unstable femur) may be 
irradiated before study initiation, provided other measurable or evaluable disease is present 
and radiation therapy is completed ≥ 4 weeks before start of therapy. All eligibility criteria for 
progression must still be met. Any other indications for radiotherapy after protocol treatment 
has begun will constitute disease progression, and the patient will stop protocol treatment (see 
Section 13.1.3). 
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12.3 
CALGB 90601 Policy Concerning the Use of Growth Factors 
12.3.1 Epoetin (EPO) 
The use of erythropoietic stimulating agents (epoetin alfa and darbepoetin) is discouraged 
in this trial due to the risk of thrombotic events associated with these medications. If an 
investigator chooses to use these medications, the guidelines of the package insert and the 
warnings and limitations associated with those agents should be followed carefully. 
12.3.2 Filgrastim (G-CSF), pegfilgrastim, and sargramostim (GM-CSF) 
1. 
Filgrastim/pegfilgrastim and sargramostim should not be used to avoid dose 
reductions or delays. 
2. 
Filgrastim, pegfilgrastim, or sargramostim, may be used for secondary prophylaxis 
following an episode of febrile neutropenia, according to the ASCO guidelines. 
3. 
If pegfilgrastim is used in CALGB 90601, it should be administered on Day 9 of 
the cycle. 
4. 
For the treatment of febrile neutropenia, the use of CSF's should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSF's 
may be indicated in patients who have prognostic factors that are predictive of 
clinical deterioration such as pneumonia, hypotension, multi-organ dysfunction 
(sepsis syndrome) or fungal infection, as per the ASCO guidelines. Investigators 
should therefore use their own discretion in using the CSF's in this setting. The use 
of CSF (filgrastim/pegfilgrastim or sargramostim) must be documented and 
reported on the CALGB C-260 Remarks Addenda 
5. 
If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
12.3.3 Oprelvekin (IL-11, Neumega®) 
The use of oprelvekin for patients enrolled in this study is discouraged. 
13.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE 
For the purposes of this study, patients with measurable and non-measurable lesions should be 
reevaluated with appropriate imaging studies every 9 weeks (every three cycles) during 
chemotherapy and treatment with bevacizumab/placebo alone, then every 3 months until 
progression. In addition to a baseline scan, confirmatory scans should also be obtained at least 4 
weeks following initial documentation of objective response. 
While all areas of malignant disease will be monitored, patients will be categorized into having 
either measurable disease or non-measurable disease.  
13.1 
Measurable Disease/Target Lesions 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques (CT, 
MRI, x-ray) or as ≥ 10 mm with spiral CT scan. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 


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All measurable lesions (up to a maximum of 10) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically). A 
sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
All other lesions, including small lesions and bone metastasis, will be identified as non-target 
lesions. (See Section 13.2. for response criteria for non-target lesions.) 
13.1.1 Complete Response (CR): Disappearance of all target lesions. Changes in tumor 
measurement must be confirmed by repeat studies (see Section 13.1.5). 
13.1.2 Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions taking as reference the baseline sum LD. Moreover, performance status 
must be stable or improved at the time that a PR is determined. Changes in tumor 
measurements must be confirmed by repeat studies (see Section 13.1.5). 
13.1.3 Progression (PD) is defined if any of the criteria below are met: 
• 
At least a 20% increase in the sum of the LDs of target lesions (taking as a reference 
the smallest sum LD recorded since the treatment started) or the appearance of one or 
more new lesions. 
• 
Development of an indication for radiation therapy while on treatment.  
13.1.4 Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as a reference the smallest sum LD since the treatment started. 
13.1.5 Confirmation Measurement and Duration of Response for Measurable 
Disease/Target Lesions 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat studies that should be at least 4 weeks after the criteria for response are first 
met. For this study, restaging is scheduled to take place every 9 weeks (every 3 cycles). 
13.1.6 Duration of Overall Response for Measurable Disease/Target lesion 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 


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13.2 
Non-target Lesions 
All other lesions (or sites of disease) not included in the “target disease” definition should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as “present” or “absent.” 
13.2.1 Complete Response (CR): Disappearance of all non-target lesions. 
13.2.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or 
more non-target lesion. 
13.2.3 Progression (PD): Appearance of one or more new lesions. Unequivocal progression 
of existing non-target lesions.  
13.3 
Cytology and Histology 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
These techniques can be used to differentiate between PR and CR in rare cases (for example, 
residual lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
13.4 
Evaluation of Best Overall Response 
The best overall response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). In general, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Notes: 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration” on the C-1764, CALGB 90601 Treatment Form under 
“other.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
• 
Early progression/Deaths: Those patients who progress or die within 3 weeks of starting 
therapy as a result of an event unrelated to their tumor or to treatment (e.g. motor vehicle 
accident) will be deemed inevaluable. 


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• 
Loss to Follow Up: Patients in whom inadequate data on response or toxicity results from 
loss of contact with the patient, will be deemed inevaluable. 
• 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
14.1 
Duration of Treatment 
14.1.1 Complete Response: Patients may discontinue therapy after achievement of a complete 
response in all response categories at the discretion of the treating physician. 
Bevacizumab/placebo may be continued until disease progression or unacceptable 
toxicity. For patients who discontinue protocol treatment, all further treatment will be at 
the physician's discretion. 
14.1.2 PR or SD: Gemcitabine and cisplatin treatment is not to exceed 6 cycles. Continue 
treatment at the highest tolerable dose until the appearance of disease progression or 
unacceptable toxicity per Section 9.0. Bevacizumab/placebo may be continued until 
disease progression or unacceptable toxicity.  
14.1.3 Disease Progression: Patients should receive a minimum of three cycles of therapy. 
Patients that have disease progression after 3 cycles of therapy based on measurable 
disease (see Section 13.1.3) or non-measurable disease (see Section 13.2.2) should be 
removed from protocol therapy. All sites of disease progression should be recorded. 
Patients will be followed for survival for up to 7 years after randomization. This study 
has been designed with no crossover permitted. Patient unblinding will occur only in 
cases of emergency (see Section 11.3). 
In the case that a patient has rapid clinical disease progression at any time during protocol 
therapy, s/he may be removed from protocol treatment by the treating physician only 
after discussion with the study chair. Document details, including tumor measurements, 
on CALGB Form C-660. Patients will be followed for secondary malignancies and 
survival. 
14.2 
Extraordinary Medical Circumstances 
If, at any time, the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. 
In this event: 
• 
Notify the Study Chair. 
• 
Document the reason(s) for discontinuation of therapy on the C-260 CALGB Remarks 
Addenda. 
• 
Follow the patient for secondary malignancies, disease response, and survival for a 
minimum of 7 years following registration. 


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14.3 
Crossover 
There is no crossover in this study. After disease progression (or termination of protocol 
therapy), bevacizumab/placebo should be discontinued and will no longer be provided. Further 
treatment is at the discretion of the patient and the treating physician. 
15.0 STATISTICAL CONSIDERATIONS  
15.1 
Endpoints 
The primary endpoint is overall survival (OS). OS will be measured from date of 
randomization to date of death due to any cause. 
Secondary endpoints will be progression-free survival (PFS), objective response rate (defined 
as confirmed complete and partial responses), and toxicity. PFS will be measured from the 
date of randomization to date of progression or death due to any cause, whichever occurs first. 
Progression and response will be defined using the RECIST criteria. 
15.2 
Stratification 
Randomization will be stratified on a) the number of negative prognostic features (0, 1) based 
on the presence or absence of visceral metastases; and b) prior chemotherapy (no, yes). 
15.3 
Power Considerations 
This is a randomized, double-blind phase III trial in which 500 patients will be randomized 
with equal probability to one of two possible treatment regimens: gemcitabine, cisplatin, and 
placebo or gemcitabine, cisplatin, and bevacizumab.  
The following calculations assume a monthly accrual rate of almost 14 patients patients/month 
accrued over a 36-month period, and will be followed for 36-months after study closure and a 
two-sided alpha level of 0.05. Survival time is assumed to follow an exponential distribution. 
With 454 deaths, the power to detect a hazard ratio of 0.74 or a 26% decrease in hazard rate 
(equivalent to an increase in median OS from 13.8 months to about 18.63 months in the 
gemcitabine, cisplatin, and placebo treatment group or gemcitabine, cisplatin, and 
bevacizumab group, respectively) is 87%. 
15.4 
Interim Analysis 
Efficacy (overall survival) analyses will be conducted on semiannual basis to coincide with the 
semiannual meetings of the Alliance Data and Safety Monitoring Board (DSMB). Under the 
alternative hypothesis, four hundred forty-five events (deaths) are expected at the end of the 
follow-up period. The first interim analysis for OS will be performed at about 28% of the full 
information (approximately 24 months after study activation). Other interim analyses will be 
performed at 41% of the full information (at approximately 30 months), at 55% (at about 36 
months), at 68% of the total information (at about 42 months), at 78% (at about 48 months), at 
86% (54 months), at 91% (at about 60 months) and at 100% (at about 72 months after study 
activation). To help insure complete data on which to base the interim analyses, institutions 
will be asked to submit survival status on their patients on a semi-annual basis. 
A group sequential design by O’Brien and Fleming will be used to stop the trial early to reject 
the null hypothesis.189 Assuming a one-sided type I error rate = 0.025 and the above percent 
information available at each look, the z-score boundaries for stopping for superiority for (OS) 
are: 3.96, 3.27, 2.83, 2.54, 2.37, 2.26, 2.20 and 2.10. The z-score boundaries for stopping for 
futility for OS under the alternative hypothesis at a fixed type I rate = 0.0025 are: –1.13, –0.78, 
–0.46, –0.20, 0.01, 0.13, 0.21 and 2.10. Should any boundary be crossed, accrual to the study 


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will be stopped. These rules have a negligible impact on the type I and II error rates of this 
trial.190  
 
 
Boundaries for Interim Analysis 
Interim 
Analysis 
Percent Information 
(number of deaths) 
For Superiority 
For Futility 
1 
28% (125) 
3.96 
-1.13 
2 
41% (182) 
3.27 
-0.78 
3 
55% (244) 
2.83 
-0.46 
4 
68% (302) 
2.54 
-0.20 
5 
78% (347) 
2.37 
-0.012 
6 
86% (382) 
2.26 
0.13 
7 
91% (405) 
2.20 
0.21 
8 (Final) 
100% (445) 
2.10 
2.10 
Table 2 
In addition, this trial incorporates a phase II PFS-based decision rule. The phase II rule will be 
implemented as follows: after the first 115 PFS events are observed the proportional hazards 
model estimate of the PFS hazard ratio will be computed and reported to the Alliance DSMB. 
The analysis based on 115 PFS events will take place at approximately 18 months after study 
activation. This is halfway through the study accrual, assuming that the accrual rate is as 
projected. As a result, it is unlikely that the trial will be accrued before the interim PFS 
analysis. If the observed hazard ratio is less than 1.2 the DSMB should recommend closing the 
study. To help insure complete data on which to base the interim analysis on the PFS endpoint, 
events (progression) should be faxed to the Alliance Statistics and Data Center within one 
week of institution's assessment of the patient's event. Institutions with patients enrolled on 
this phase III study that do not submit PFS in a timely manner may be denied future 
registration to the study. Furthermore, the progression endpoint will be reviewed for 
completeness of data in the database at about 50% of accrual. The trial will remain open if the 
number of progression events is at 115. If the number of progression events is lower than the 
target of 115, the trial will be suspended to further accrual until the database is updated to 
permit the futility analysis to be performed. 
15.5 
Toxicity Monitoring 
Monthly conference calls (including the Study Chair, Committee Chair, study statisticians, 
data coordinator, protocol coordinator, and Alliance Executive Officer) will be held to monitor 
the first 120 patients for 4 cycles for early stopping due to unacceptable treatment-related 
events. Unacceptable toxicity will be defined as: treatment-related death; grade 4 febrile 
neutropenia; any treatment-related irreversible grade 3 or 4 toxicity excluding nausea and 
vomiting (irreversible toxicity will be defined as grade 3 or greater toxicity that persists at 
grade 3 or higher for more than one cycle of treatment); any treatment-related grade 3 or 
higher arterial thrombotic event; grade 3 or higher CNS hemorrhage; treatment-related grade 3 
or higher hemorrhage other than hematuria; or grade 3 or higher gastrointestinal perforation. 
Grade 3 uncomplicated deep venous thrombosis which does not require invasive or 
thrombolytic intervention will not be considered an irreversible adverse event. Institutions will 
be asked to submit electronically or fax toxicity forms after each cycle of treatment (every 21 
days). Institutions with patients enrolled on this phase III study that do not submit toxicity in a 
timely manner may be denied future registration to the study.  


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Furthermore, the study will be monitored for deaths, particularly among the first 60 patients 
randomized to Arm B.  If the observed proportion of treatment-related deaths exceeds 10% by 
at least one standard error, accrual will be immediately suspended to the trial. 
It is assumed that the incidence of unacceptable toxicity in patients treated with gemcitabine 
and cisplatin arm is 18%. If at any scheduled time of analysis the lower boundary of a one-
sided 90% confidence interval for the difference in unacceptable toxicity exceeds 10%, accrual 
to the trial will be immediately suspended. The trial will remained closed until the review of 
all toxicity data is completed and a decision is made about whether it is safe to resume accrual. 
This decision will be made by consensus of the study team, the Alliance DSMB and CTEP. 
15.6 
Data Analysis 
An intent-to-treat approach will be used in this phase III study to analyze OS. Patients who 
withdraw consent or withdraw from the study due to toxicity will continue to be followed for 
survival, even if they begin another therapy. The Kaplan-Meier product-limit estimator will be 
used to estimate the OS, and PFS.191 The stratified log-rank statistic will be the primary 
analysis to compare the two treatment arms on OS with the stratification factors: presence of 
visceral metastases (no, yes) and prior chemotherapy (no, yes).192 In addition, the proportional 
hazards model will be used to assess the importance of the treatment arm adjusting on patient 
characteristics, stratification variables and other important covariates in predicting OS.193  
PFS will be measured from the date of randomization to date of progression or death due to 
any cause, whichever occurs first. Progression will be defined using the RECIST criteria. Data 
for patients without disease progression or death at the time of analysis will be censored at the 
time of the last tumor assessment (or, if no tumor assessments were performed after the 
baseline visit, at the time of randomization plus 1 day).  Data for patients who receive 
non-protocol-specified anti-cancer therapy prior to experiencing documented disease 
progression will also be censored at the time of the last tumor assessment prior to receiving the 
non-protocol-specified therapy.  The primary analysis of PFS will be a two-sided stratified 
log-rank test comparing Arm A and Arm B.  The stratification factors will consist of the two 
stratification factors used for patient randomization:  prior nephrectomy (yes vs. no) and 
Motzer score (0 vs. 1-2 vs. 3+).  Results from unstratified log-rank tests will also be provided.  
Kaplan-Meier methodology will be used to estimate median PFS for each treatment arm. 
Furthermore, the Cochran-Mantel-Haenszel test will be used to compare the two arms on the 
proportion of patients who experience an objective response (defined as either a confirmed CR 
or a PR) adjusting on the stratification factors [presence of visceral disease (no, yes) and prior 
chemotherapy (no, yes)]. In addition, the Fisher exact test will be used to compare the two 
treatment arms on the proportion of patients with unacceptable treatment related grade 3 or 
higher toxicity. 
15.7 
Accrual and Follow-up 
Based on previous data from patients enrolled on CALGB 90102, the projected accrual rate is 
2.6 patients per month. However, the accrual is anticipated to be higher as the study would 
also be opened through the CTSU. Assuming an accrual rate of about 14 patients/month, 
accrual is expected to be completed in about 36 months within study activation. This rate is 
reasonable as we have obtained commitments to participate in this trial from ECOG, SWOG, 
and other institutions through the CTSU. All patients will be followed for a maximum period 
of 7 years after randomization. 


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Statistical considerations for correlative sciences studies 
15.8 
Serum and tissue-based biomarker studies 
15.8.1 Power Computations 
The target sample size for this study is 500 patients with metastatic transitional cell 
carcinoma. Power computations are computed based on the primary objectives (10.1.2 
and 10.2.2) and are presented assuming that 80% (n = 400) of the samples will be 
available. Because we are testing two primary hypotheses (10.1.2 and 10.2.2), each 
hypothesis will be tested with a significance level of 0.025. The plasma levels will be 
dichotomized at the median level and patients will be classified as having either low 
(below or equal the median) or high (above the median) levels. With 400 samples, the 
log-rank statistic has 80% power to detect a HR=1.42. The power computations are based 
on the following assumptions: the survival distribution time follows an exponential 
distribution, an accrual rate of about 12 patients/month, 36-months accrual period, 36 
months post-accrual follow-up, a two-sided significance level of 0.025 and the median 
survival time among patients with high VEGF levels is 13.8 months.  
In addition, power computations for testing treatment by marker interaction are provided 
in the Table 3, below. Adequate power will be detected for only very large interactions 
terms. The table below presents the power for testing the null of no treatment by marker 
interaction using a two-sided level of significance of  a = 0.05 and assuming positive 
prevalence of 0.30 and 0.50 in the markers. The assumed median OS for is 13.8 for the 
gemcitabine and cisplatin only arm. No discrepancy in OS distributions of the markers is 
expected for this treatment arm. If there is a suggestion that there are treatment by marker 
interactions, then the estimates of HR and 95% CI will be presented separately within 
each treatment group. 
Prevalence of Positive 
Marker 
∆12 
∆22 
Power 
0.50 
1.1 
2.2 
0.90 
 
1.1 
2.1 
0.86 
 
1.1 
2.0 
0.80 
 
1.2 
2.2 
0.80 
 
1.2 
2.1 
0.74 
 
1.2 
2.0 
0.67 
0.30 
1.1 
2.2 
0.84 
 
1.1 
2.1 
0.79 
 
1.1 
2.0 
0.73 
 
1.2 
2.35 
0.82 
 
1.2 
2.3 
0.79 
 
1.2 
2.2 
0.74 
Table 3 
Quality Control: A sample of 40 (10% of 400) specimens will be used to assess the 
reproducibility of the VEGF plasma assays. Inter-batch and intra-batch variation (based 
on duplicate samples) will be estimated by splitting the 40 specimens into two batches. If 
the between correlation coefficient between the VEGF replicates is at least 0.8, then the 
assay will be considered “reproducible.” However, if the correlation coefficient is less 
than 0.80, the study team will discuss how to proceed with these assays. 


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Recommendations may include modifying the assay, or training the laboratory personnel 
who are performing these assays. The reproducibility rates will be reported at the end of 
the study. 
15.8.2 Data Analysis  
The Kaplan-Meier product-limit method will be used to estimate the survival distribution 
by the plasma VEGF dichotomized at the median level. We will use the log-rank test 
statistic to compare the low and high VEGF levels. Furthermore, the proportional hazards 
regression model will be used to test if plasma VEGF levels are prognostic factors of 
overall survival adjusting for the baseline covariates and other known prognostic factors. 
Because of the multiplicity of analysis, we will use the Bonferroni correction to adjust on 
the type I error rate. A type I error rate of 0.025 will be used for the primary analyses 
based on survival time by plasma VEGF level dichotomized below the median. For all 
secondary data analysis, a type I error rate = 0.05 will be used. 
15.8.3 TMA Evaluation 
Potential biomarkers will be identified based on their associations with PFS or OS in both  
and in either arm of the trial controlling for the number of comparisons using the method 
of Jung et al.194 In addition, the proportional hazard models will be used to test if certain 
markers will predict PFS or OS. Furthermore, the proportional hazards model will be 
used to explore if treatment arm, gene expression and gene expression-arm interaction 
terms, adjusting for stratification variables and other important clinical variables, even 
though this study is not powered to detect except large interaction terms. Furthermore, 
the proportional hazards model will be used to explore if 118C/T and C8092A 
polymorphisms adjusting on treatment and polymorphisms-arm interaction will predict 
clinical outcomes (PFS and OS). 
We plan to perform a secondary, subgroup analysis of the association between markers of 
DNA repair mechanisms and outcome in primary tumors and metastatic tumors to 
determine if there are large differences in the degree of association. The data will not be 
combined if these analyses show statistical differences of p-value < 0.10. Estimates of the 
hazard ratio and 95% CI for the hazard ratio will be reported within each group. 
Unsupervised clustering will be used to identify clusters that may be associated with 
survival. The log-rank test will be used to quantify discrepancy in survival profiles 
among the clusters. In addition, we will use a method proposed by Li and Luan.195 
For scoring of the majority of markers, including ERCC1, Rad51, RRMI, BRCA1, 
BRCA2, and caveolin-1, specimens will be graded from 0 to 3+ intensity representing the 
range from no staining to heavy staining, as previously reported (3-18). The overall 
percentage of cancer cells showing staining (0-100%) will also be reflected in the score 
as follows:  
0: 
No reactivity 
1+: Weak reactivity, with 0-10% of tumor cells showing positive staining. 
2+:  Moderate activity, with 10-50% of tumor cells showing positive staining. 
3+:  Strong reactivity, with > 50% of tumor cells showing positive staining.  
All comparisons of staining intensities and percentages will be made at 200X 
magnification.  
For Immunofluorescence of Rad51, each tumor will be scored as having the Rad51-
containing nuclear foci absent (0) or present (1). 


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Furthermore, unconditional logistic regression model will used to test if markers will 
predict response and resistance to bevacizumab/cisplatin/ gemcitabine. 
15.9 
Statistical considerations for the evaluation of the effect of tobacco on bladder cancer 
outcomes 
15.9.1 Endpoints 
Primary: Overall survival (by smoking status, as determined by patient report). 
Overall survival was chosen as the primary endpoint rather than cancer-specific survival, 
despite the widely recognized deleterious effects of tobacco use on non-cancer related 
causes of death, such as cardiovascular disease, because of the difficulty in definitively 
establishing whether the cause of death is cancer-related.   
Secondary: Correlation between smoking status by patient report and VEGF levels.  
Variables with possible effects on VEGF levels include obesity, renal disease, 
hypertension, diabetes, and cardiovascular disease.196 In accordance, data will be 
collected on the following: height and weight (to determine BMI), estimated creatinine 
clearance using the Cockcroft-Gault equation, blood pressure, history of diabetes and 
cardiovascular disease, cardiovascular events during the course of the study, chronic 
infections, and infections during the course of the study. 
Secondary: Association between patient-reported tobacco use and serum cotinine 
levels. Cotinine levels have been validated as an accurate method of assessing tobacco 
usage. To assess the accuracy of obtaining tobacco usage information by patient survey, 
the association between smoking status as determined by cotinine level and smoking 
status by patient report will be determined. 
15.9.2 Power Computations 
The primary objective is to determine if tobacco use is associated with overall-survival 
(OS). Overall survival is defined from the date of randomization until date of death due to 
any cause. The smoking prevalence in the US in men in 2007 was 23.9%. Smoking 
prevalence for the entire population (men and women) varies by major metropolitan area 
and is as low as 15% in California and as high as 23% in other cities with Alliance sites, 
such as Chicago and Raleigh-Durham.197 The prevalence of current tobacco use in 
patients with bladder cancer in a case control study in Maine, New Hampshire, and 
Vermont was 32%, whereas the smoking prevalence for an unselected population in these 
states ranges from 18-20%.198   
Tobacco use will be determined based on the cotinine levels among patients with 
available serum samples. A patient with serum cotinine levels greater than 3.08 ng/mL 
will be considered a tobacco user. We neither know the prevalence of tobacco users nor 
the number of available serum samples in patients who will be randomized to CALGB 
90601. We anticipate that this correlative science component will be activated in the next 
year. We project that the remaining number of patients to be randomized to CALGB 
90601 is 350. We anticipate that 86% of the 350 patients who will be randomized to 
CALGB 90601 will consent to provide serum based on our experience from other 
Alliance GU correlative sciences studies. Table 1 presents the minimum hazard ratio 
(HR) detectable assuming event (death) rates of 0.80-0.90, tobacco use prevalence of 
0.15-0.35, a two-sided type I error rate of 0.05, 80% power for the log-rank statistic and 
the OS endpoint follows an exponential distribution.  


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Event rate among 300 patients who will have 
consented to give serum 
Prevalence of tobacco use 
80% 
85% 
90% 
0.15 
1.66 
1.63 
1.61 
0.20 
1.57 
1.55 
1.53 
0.25 
1.52 
1.50 
1.48 
0.30 
1.48 
1.47 
1.45 
0.35 
1.46 
1.44 
1.43 
Table 4 
Minimum detectable HR under a range of prevalence of tobacco use rates and death rates 
assuming a two-sided type I error rate = 0.05 and 80%  power. 
15.9.3 Data analysis 
The Kaplan-Meier191 product limit method and the log-rank statistic will be used to 
estimate and to test the OS distribution by tobacco use, respectively. Moreover, the 
proportional hazards model193 will be used to assess the prognostic importance of tobacco 
use in predicting OS adjusting on treatment arm, baseline characteristics and stratification 
factors (presence of visceral metastases and prior chemotherapy).  In addition, 
exploratory analyses will be performed where the incidence of infection, as well as other 
factors that can affect VEGF levels, such as, creatinine clearance, BMI, blood pressure, 
and the presence of cardiovascular disease will be considered as potential predictors of 
overall survival. Furthermore, the proportional hazards model will be used to test for 
treatment, tobacco use, and treatment by tobacco use interaction. Estimates of HR and 
95% CI will be presented separately within each treatment arm if there is a suggestion 
that there is a treatment-tobacco use interaction.  For objective 2, analysis of variance will 
be used to test differences in VEGF levels due to smoking if the cotinine levels follow a 
normal distribution. Otherwise, the Kruskal-Wallis rank sum statistic will be used to test 
for difference in VEGF levels by smoking. The kappa statistic to estimate the 
concordance between patient reported smoking status and tobacco use as measured by the 
serum cotinine level will be used. 
15.10 Pharmacogenomic analysis 
The primary objective of the pharmacogenetic portion of this study is the genotype (CT/TT 
versus CC) and treatment (GC versus GCB) interaction in predicting OS. This analysis will be 
carried out within the framework of a two-way multiplicative log-linear Cox model whose 
canonical hazard function can be presented as l[z|t]= l0[t]exp[b1Z1+b2Z2+b12Z1Z2] (Z1=0 if 
CC/TT and 1 otherwise, Z2=0 if GC and 1 otherwise). 
For notational simplicity, we will denote individuals with CT or TT genotypes by group 1 and 
individuals with CC genotypes as group 2 and the two treatment arms by A (GC) and B 
(GCB). Out of the 500 patients accrued to the study, we expect to have about 400 (roughly 
80%) available for pharmacogenomic sampling. The putative prevalence rates for groups 1 and 
2 are p1 = 0.29 and p2 = 0.71 respectively (Krippl et al, 2003). The expected cell counts are 
provided in Table 5. 


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nA1 
nA2 
nB1 
nB2 
58 
142 
58 
142 
Table 5 
The power of the Wald test for testing the hypothesis H0: b12=0, at a two-sided level of 
significance of  a = 0.05, is presented for a number of examples in Table 5 (results are based 
on 10000 simulations for each case). Needless to say, given the relatively small sample size, 
only 
very 
large 
interactions 
will 
be 
detectable 
with 
adequate 
power. 
The 
assumed/hypothesized median OS for the treatment arms are MA=13.8 and MB=18.68 months 
respectively. On arm A (GC) no discrepancy in the OS profiles of the genotypes is expected 
(i.e., l1A= l2A = log[2]/13.8 assuming exponential survival). For group 1, ∆1B denotes the 
improvement, compared to treatment A (GC), in survival (hazard ratio) for receiving treatment 
B (GCB). 
 
l1A 
l2A 
∆1B 
∆2B 
Power 
0.0502 
0.0502 
1.1 
2.1 
0.84 
0.0502 
0.0502 
1.1 
2.0 
0.75 
0.0502 
0.0502 
1.1 
1.9 
0.65 
0.0502 
0.0502 
1.2 
2.1 
0.68 
0.0502 
0.0502 
1.2 
2.0 
0.61 
0.0502 
0.0502 
1.2 
1.9 
0.52 
Table 6 
Secondary Objectives:  We will also look at the above questions in the context of other 
genotypes in additional candidate genes of putative importance. We will also carry other 
exploratory analyses based on other clinical endpoints (e.g., PFS, tumor response and toxicity). 
The association between genes implicated in gemcitabine metabolism, transporter and clinical 
phenotype (systemic toxicity, response, and survival) will be performed. 
 
16.0 ADVERSE EVENT REPORTING (AER) 
Investigators are required by Federal Regulations to report serious adverse events as defined in the 
table below. Investigators are required to notify the Investigational Drug Branch, the Study Chair, 
and their Institutional Review Board if a patient has a reportable adverse event. The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for serious AE reporting beginning April 1, 2018. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
All 
reactions 
determined to be “reportable" in an expedited manner must be reported using the CTEP Adverse 
Event Reporting System (CTEP-AERS), accessed via the CTEP website, https://eapps-
ctep.nci.nih.gov/ctepaers. 
In the rare occurrence when Internet connectivity is lost, an AE report may be submitted using 
CTEP’s Adverse Event Expedited Report – Single Agent or Multiple Agent paper template 
(available at http://ctep.cancer.gov) and faxed to 301-230-0159. A 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497, only when Internet connectivity is disrupted. Once 
Internet connectivity is restored, an AE report submitted on a paper template or a 24-hour 


CALGB 90601 
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notification phoned in must be entered electronically into CTEP-AERS by the original submitter at 
the site. 
The reporting of adverse events described in the table below is in addition to and does not supplant 
the reporting of adverse events on study-specific adverse event forms (see Section 6.1 for required 
forms). 
Please note: Adverse event reporting on the CALGB 90601 study forms uses CTCAE version 3.0.  
However, adverse events that require reporting via CTEP-AERS utilize CTCAE version 5.0. 
16.1 
CALGB 90601 Reporting Requirements: 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND: CTEP-AERS Expedited 
Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of 
Treatment 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpecte
d  
Expecte
d 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hrs; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is 
required as outlined in the table. 
March 2005 
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause should be provided. 
•Expedited AE reporting timelines defined: 
Ø “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 5 calendar days of the initial 24-hour report. 
Ø “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 


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• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
16.2 
Additional instructions or exclusions 
Additional instructions or exclusions from CTEP-AERS expedited reporting 
requirements for phase 2 and 3 trials utilizing an agent under a CTEP-IND: 
• 
CALGB 90601 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (either 
treatment arm) in this trial. 
• 
For the purposes of expedited adverse event reporting, the CAEPR (which includes 
expected adverse events) for bevacizumab may be found in Section 16.3, below. Expected 
adverse events for gemcitabine and cisplatin may be found in Sections 11.1 and 11.2, and 
the package inserts. Note: The ASAEL column of the CAEPR has been replaced with the 
specific protocol exceptions to expedited reporting (SPEER) list. This list now includes 
‘expected’ severity grades in addition to event terms. 
• 
A discussion of the adverse events associated with the agents used in this trial can be 
found in Section 11.0 (Drug Formulation, Availability and Preparation).  
• 
Grade 3/4 myelosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. 
• 
Grade 3/4 nausea or vomiting, or grade 3/4 neurotoxicity and hospitalization resulting 
from such do not require CTEP-AERS, but should be submitted as part of study results. 
• 
Grade 3/4 hematuria or hospitalization resulting from such do not require CTEP-AERS, 
but should be submitted as part of study results. 
• 
When evaluating hypertension, consider the description of severity grade 3 relative to the 
last AE reporting period. That is, for “more than one drug or more intensive therapy than 
previously used,” “previously” should be considered the last reporting period. A regimen 
more intensive than a previous reporting period need only prompt expedited reporting the 
first time that it is used. If BP is stable on the more intensive regimen, do not continue to 
report grade 3 HTN via CTEP-AERS. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
• 
Secondary malignancy: A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A secondary malignancy is not considered a metastasis of the initial 
neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. In CTCAE version 5.0, 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. 


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•     Second malignancy: A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting unless otherwise specified. 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the report of the results of the clinical 
trial, e.g., study summary forms or cooperative group data reporting forms (see Section 6.1 
for required forms). 
•     In CTCAE v5.0, pregnancy loss is defined as “Death in utero,” and any pregnancy loss 
should be reported expeditiously as Grade 4 “Pregnancy loss” under the Pregnancy, 
puerperium and perinatal conditions SOC. A pregnancy loss should NOT be reported as a 
Grade 5 event under the Pregnancy, puerperium and perinatal conditions SOC as currently 
CTEP-AERS recognizes this event as a patient death. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General Disorders and Administration SOC. 
16.3 
 
 
 
 
 
 
  
 
 
 
 
 
 
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APPENDIX I 
 
Clinical Trials Agreement 
 
 
The bevacizumab and placebo supplied by CTEP, DCTD, NCI used in this protocol are provided to 
the NCI under a Collaborative Agreement (CRADA, CTA) between Genentech Inc. (hereinafter 
referred to as “Collaborator” and the NCI Division of Cancer Treatment and Diagnosis. Therefore, 
the following obligations/guidelines, in addition to the provisions in the “Intellectual Property 
Option to Collaborator” (at http://ctep.cancer.gov/industry) contained within the terms of award, 
apply to the use of bevacizumab in this study: 
1. Bevacizumab/placebo may not be used for any purpose outside the scope of this protocol, nor 
can it be transferred or licensed to any party not participating in the clinical study. 
Collaborator’s data for bevacizumab are confidential and proprietary to Collaborator and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI. If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a confidentiality 
agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol in which there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order. Additionally, all Clinical Data 
and Results and Raw Data will be collected, used and disclosed consistent with all applicable 
federal statutes and regulations for the protection of human subjects, including, if applicable, 
the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. 
Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 


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5. Any data provided to Collaborator(s) for phase III studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for the clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group Office for immediate delivery to Collaborator for advisory review and comment prior to 
submission for publication. Collaborator will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 
30 days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator’s intellectual property rights, are protected. Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting 
or publication in the proceedings. Press releases and other media presentations must also be 
forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
NCI Shady Grove 
Room 5W-520, MSC 9740 
9609 Medical Ctr. Dr. 
Bethesda, MD 20892-9740 
FAX 240-276-7894 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator. No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/proprietary information. 
 
 
 
 


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APPENDIX II 
UPC (Urine Protein to Creatinine) Ratio 
 
 
The UPC (urine protein to creatinine) ratio directly correlates with the grams of protein found in a 24 hr 
urine. The UPC ratio can be used in place of a 24-hour urine. 
 
 
Procedure for Obtaining a Urine Protein/Creatinine Ratio: 
 
1. Obtain at least 4 mL of a random urine sample in a sterile container (does not have to be a 
24-hour urine sample). 
2. Determine protein concentration (mg/dL). 
3. Determine creatinine concentration (mg/dL). 
4. Divide #2 by #3 above: 
 
 
UPC Ratio = 
 
Protein Concentration (mg/dL) 
Creatinine Concentration (mg/dL)