Clinical trial NCT00794950
Conditions: Urinary Tract Urothelial Carcinoma
Keywords: Bladder Cancer High Risk Non-muscle Invasive Lower Urinary Tract Urothelial Carcinoma
Sponsor: University of Michigan
Start date: 2009-01-01; Completion date: 2016-08-22
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A majority of patients with bladder cancer have disease confined to the inner lining of the bladder. Patients with high risk features (high grade tumors, tumors invading into a deeper superficial layer) are routinely treated with Bacillus Calmette Guerin (BCG) instilled in their bladder after the tumor has been removed. While up to 55% of patients respond to BCG, failure to respond may suggest a more aggressive tumor that requires more definitive therapy with complete bladder removal. BCG is believed to work by stimulating the body's own immune system to attack tumor cells. It may also work by blocking the machinery that tumors use to grow blood vessels which fuel tumor growth. A newer oral drug, sunitinib has shown to help patients with metastatic bladder cancer by blocking new blood vessel growth (VEGF inhibition). The investigators are studying the use of BCG followed by sunitinib in patients with high risk non-muscle invasive bladder cancer to evaluate the complete response (no visible evidence of tumor in the bladder) at 3 months and 6 months. The investigators will also evaluate whether there is recurrent tumor at three years.

Detailed description:
Despite a complete response of 45-55% in patients with non-muscle invasive urothelial carcinoma involving the lower urinary tract at 3 months, many patients suffer from multiple recurrences and progression in up to 1/3 of patients. While radical cystectomy is an effective local therapy for patients with high risk non-invasive disease, roughly 15% of patients will still develop progression. More importantly, the morbidity of radical cystectomy as described above represents a barrier to treatment in some individuals. Thus, there is a real need to identify newer therapies that reduce morbidity and improve outcomes in patients with non-invasive urothelial cancer. While multiple drug regimens have been the standard for many forms of cancer including invasive bladder cancer, few reports exist on multidrug regimens for non-invasive bladder cancer.

The fundamentally agreed upon mechanism of action of BCG intravesical therapy for superficial bladder cancer is the generation of a non-specific immune response with the expression of cytokines by inflammatory cells resulting in tumor death. Cytokines produced by BCG therapy such as IFNα may block vascular endothelial growth factor (VEGF) which is expressed in superficial and invasive bladder cancer and may provide a mechanism for disease progression.

Sunitinib is an oral tyrosine kinase inhibitor that blocks VEGF. Recent reports demonstrate clinical response in patients with metastatic bladder cancer treated with sunitinib after recurrence following standard chemotherapeutic regimens. The addition of sunitinib following BCG in order to consolidate VEGF inhibition may result in superior 3 month complete response rates. We know that patients who have a complete response to BCG at 3 months have improved disease.

Arms: arm 1: Intravesical BCG (81 mg Theracys BCG in 50 ml normal saline) once weekly for 6 weeks within 6 weeks of bladder biopsy confirming high risk non-muscle invasive urothelial carcinoma.
Interventions: intervention 1: Sunitinib
Intervention descriptions: intervention 1: Patients are treated with a 6-week induction course of intravesical bacillus Calmette-Guerin (BCG) followed by a 2 week rest period and 4 week course of oral Sunitinib.

Patients will receive intravesical BCG (81 mg Theracys BCG in 50 ml normal saline) once weekly for 6 weeks within 6 weeks of bladder biopsy confirming high risk non-muscle invasive urothelial carcinoma. Two weeks after completion of BCG, patients will receive Sunitinib (50 mg daily) continuously for 28 days followed by a two week rest period. Patients will be reassessed with transurethral resection and urine cytology. Those with residual/recurrent disease will receive a second course identical to the initial protocol. Those with a complete response following initial or second treatment will be placed on maintenance BCG (3 week course every 6 months for 2 years). Those failing (progression, intolerance) initial/secondary treatments will be offered alternative therapy.

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol for NCT00794950 
A Phase II Multicenter Study of Intravesical bacillus Calmette-Guerin Followed 
by Sunitinib for the Treatment of High Risk Non-muscle Invasive Lower 
Urinary Tract Urothelial Carcinoma of the Urinary Bladder 
 
Version approved by IRBMED on 10/10/2013 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
 
 
A Phase II Multicenter Study of Intravesical bacillus Calmette-Guerin 
Followed by Sunitinib for the Treatment of High Risk Non-muscle 
Invasive Lower Urinary Tract Urothelial Carcinoma of the Urinary 
Bladder 
 
 
Principal Investigator: 
 
 
Alon Z. Weizer, MD 
7312 CCC 
1500 E. Medical Center Drive, SPC 5946 
Telephone: (734)615-6662 
Fax: (734)647-9480 
aweizer@umich.edu 
 
 
 
 
 
 
Co-Investigators: 
Cheryl T. Lee, MD 
David P. Wood, Jr, MD 
Khaled Hafez, MD 
Brent Hollenbeck, MD 
James E. Montie, MD 
Maha H. Hussain, MD 
L. Priya Kunju, MD 
Nancy Rodriguez-Galano, NP 
David Smith, MD 
 
 
Statistician: 
 
 
 
Study Coordinator: 
 
Stephanie Daignault, MS 
 
 
 
Linda Drnek, CCRP 
University of Michigan Cancer Center  
 
Clinical Trials Office  
300 North Ingalls, NI8D11 
 
 
 
Department of Urology 
Telephone: 734-647-3271 
 
 
 
Telephone: 734-936-5754 
sfaruzzi@med.umich.edu 
 
 
 
Fax: 734-763-4349 
 
 
 
 
 
 
 
lagius@med.umich.edu 
 
 
 
 
 
 
Protocol Type / Version # / Version Date 
__Original / Version 8 / August 7, 2013 


1 
 
SCHEMA 
 
 
 
Cycle 1: BCG followed by 
Sunitinib 
Cycle 2: BCG followed by 
Sunitinib 
Maintenance BCG 
Alternative treatments per 
treating clinician 
Incomplete Response/ Recurrence 
Complete Response 
Recurrence/Progression 
Complete Response 
Progression 
TURBT = CIS, TaG3, and/or 
any T1 completely resected, 
eligibility criteria met 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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CONTENTS 
SCHEMA ........................................................................................................................................................................................1 
CONTENTS ...................................................................................................................................................................................2 
PROTOCOL SUMMARY ............................................................................................................................................................6 
1. 
OBJECTIVES ......................................................................................................................................................................8 
Primary Objective: ..............................................................................................................................................................8 
Secondary objectives of the trial: ..................................................................................................................................8 
2. 
BACKGROUND .................................................................................................................................................................8 
2.1 
Non-muscle Invasive Urothelial Carcinoma of the Lower Urinary Tract ........................................8 
2.2 
Angiogenesis and Urothelial Cancer ........................................................................................................... 10 
2.3 
Bacillus Calmette-Guerin and Urothelial Carcinoma ............................................................................ 11 
2.4 
Sunitinib (Sunitinib malate) ........................................................................................................................... 12 
2.5 
Rationale ................................................................................................................................................................ 14 
2.6 
Correlative Studies Background ................................................................................................................... 15 
3. 
PATIENT SELECTION ................................................................................................................................................ 16 
3.1 
 Inclusion criteria ................................................................................................................................................ 17 
3.2 
 Exclusion Criteria .................................................................................................................................................2 
3.3 
Inclusion of Women and Minorities ...............................................................................................................3 
4.0 
PRETREATMENT EVALUATION ...........................................................................................................................3 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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4.1 
Clinical ........................................................................................................................................................................3 
4.2 
Laboratory: ..............................................................................................................................................................3 
4.3 
Imaging and Diagnostic Studies:......................................................................................................................4 
4.4 
Electrocardiogram. ...............................................................................................................................................4 
4.5 
MUGA SCAN .............................................................................................................................................................4 
5.0 
REGISTRATION PROCEDURES..............................................................................................................................4 
5.1 
General Guidelines ................................................................................................................................................4 
6. 0 
TREATMENT PLAN ....................................................................................................................................................4 
6.1 
BCG ..............................................................................................................................................................................4 
6.1.1 
Dose levels ......................................................................................................................................................4 
6.1.2 
BCG administration .....................................................................................................................................5 
6.1.3 
Concomitant Medication(s) .....................................................................................................................5 
6.1.4 
DOSE reductions ...........................................................................................................................................5 
6.1.5 
Supportive Care Guidelines .....................................................................................................................6 
6.2 
Sunitinib ...................................................................................................................................................................6 
6.2.1 
Dose levels ......................................................................................................................................................6 
6.2.2 
Sunitinib administration ...........................................................................................................................7 
6.2.3 
Concomitant Medication(s) .....................................................................................................................7 
6.2.4 
Dose reductions ............................................................................................................................................7 
6.2.5 
 Supportive Care Guidelines ....................................................................................................................7 
7.0 
  DURATION OF THERAPY ......................................................................................................................................8 
7.1 
BCG ..............................................................................................................................................................................8 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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7.2 
SUNITINIB ................................................................................................................................................................8 
8.0 
CRITERIA FOR REMOVAL FROM STUDY: .........................................................................................................9 
9.0 
DURATION OF FOLLOW-UP ...................................................................................................................................9 
10.0 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................................................9 
10.1 
TICE BCG ................................................................................................................................................................ 10 
10.1.1 
Delays ............................................................................................................................................................ 10 
10.1.2 
Reduction ..................................................................................................................................................... 10 
10.2 
SUNITINIB ............................................................................................................................................................. 11 
10.2.1 
Dose Reduction for SUNITINIB ........................................................................................................... 11 
11.0 
PHARMACEUTICAL INFORMATION ................................................................................................................ 13 
11.1  TICE™ BCG ................................................................................................................................................................ 13 
11.1.1 
Agent Ordering........................................................................................................................................... 14 
11.2 
PHARMACEUTICAL INFORMATION: SUNITINIB .................................................................................. 14 
11.2.1 
Agent Ordering........................................................................................................................................... 16 
11.2.2 
Agent Accountability ............................................................................................................................... 16 
12.0 
CORRELATIVE STUDIES ....................................................................................................................................... 16 
13.0 
STUDY CALENDAR:................................................................................................................................................. 18 
14.0 
MEASUREMENT OF EFFECT ............................................................................................................................... 20 
14.1 
Definitions ............................................................................................................................................................. 20 
14.2 
Guidelines for documenting Residual disease, recurrence, progression, or metastases ....... 21 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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14.3 
Response Criteria ............................................................................................................................................... 22 
14.4 
Duration of Response ........................................................................................................................................ 22 
15.0 
REGULATORY AND REPORTING REQUIREMENTS ................................................................................... 23 
15.1 
Expedited Adverse Event Reporting ........................................................................................................... 23 
15.2 
Data Reporting ..................................................................................................................................................... 25 
16.0 
STATISTICAL CONSIDERATIONS ...................................................................................................................... 26 
16.1 
Study Design/Endpoints .................................................................................................................................. 26 
16.2 
Analyses ................................................................................................................................................................. 27 
16.3 
Patient Accrual .................................................................................................................................................... 27 
16.4 
Reporting and Exclusions ................................................................................................................................ 27 
16.4.1 
Evaluation of toxicity ............................................................................................................................... 28 
16.4.2 Evaluation of response ................................................................................................................................ 28 
17. 
DATA MANAGEMENT AND MONITORING .................................................................................................... 28 
17.1 
DATA COLLECTION/ENTRY .......................................................................................................................... 28 
17.2 
DATA SECURITY AND CONFIDENTIALITY .............................................................................................. 28 
17.3 
QUALITY ASSURANCE/DATA AND SAFETY MONITORING .............................................................. 28 
17.3.1 
Data Safety and Monitoring .................................................................................................................. 29 
18.0 
REFERENCES ............................................................................................................................................................. 30 
APPENDICIES .......................................................................................................................................................................... 34 
APPENDIX A: Performance Status Criteria ............................................................................................................. 34 
APPENDIX B: NURSING PROTOCOL FOR ADMINISTRATION OF .................................................................. 35 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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APPENDIX C: MEDICATION DIARY ........................................................................................................................... 36 
Appendix D: Site Drug Request Form ....................................................................................................................... 37 
Appendix E: Serious Adverse Event Fax Cover Sheet......................................................................................... 39 
Appendix F: SELECTED Potential CYP3A4 Drug Interactions ........................................................................ 40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL SUMMARY  
1. Objectives:  
The primary objective of this study is to determine the complete response rate (negative 
bladder biopsy, negative urine cytology, normal exam under anesthesia) at 3 months in high 
risk non-invasive urothelial carcinoma of the lower urinary tract (bladder, prostatic urethra) 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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patients treated with a 6-week induction course of intravesical bacillus Calmette-Guerin 
(BCG) followed by a 2 week rest period and 4 week course of oral Sunitinib.   
Secondary objectives of the trial:   
a. Determine the percentage of patients with high risk non-muscle invasive urothelial 
carcinoma of the lower urinary tract (bladder, prostatic urethra) with a complete 
response (negative bladder biopsy, negative urine cytology, normal exam under 
anesthesia)  at 6 months treated with a 6-week induction course of intravesical 
bacillus Calmette-Guerin (BCG) followed by a 4 week course of oral Sunitinib +/- a 
second course of BCG followed by Sunitinib.   
b. To assess the recurrence-free survival of patients treated with BCG followed by 
Sunitinib at 2 years with an intact bladder. 
c. To determine toxicity related to treatment with BCG followed by Sunitinib.   
Correlative objectives of trial:  To correlate changes in VEGF, VEGFR, p53, and other 
cytokine expression in the voided urine and/or serum with response in patients treated with 
BCG followed by Sunitinib.  
2. Rationale: 
This study is based on the concept that angiogenesis and vascular endothelial growth factor 
play a role in disease progression in patients with lower urinary tract non-muscle invasive 
urothelial carcinoma.  Treatment with BCG is likely to target this pathway and consolidating 
treatment with Sunitinib, a VEGF receptor inhibitor may improve the complete response rate 
in this population which currently is approximately 45-55% at 3 months.   
3. Primary Statistical Endpoint:   
The primary endpoint of this phase II trial is to determine the complete response rate at 3 
months as assessed by negative bladder biopsy, negative urine cytology, and normal exam 
under anesthesia of patients treated with a 6 week induction course of BCG followed by a 4-
week course of Sunitinib.    
4. Schedule:  
Patients will receive intravesical BCG ( 50mg TICE BCG in 50 ml normal saline) once weekly 
for 6 weeks within 6 weeks of bladder biopsy confirming high risk non-muscle invasive 
urothelial carcinoma.  Two weeks after completion of BCG, patients will receive Sunitinib (50 
mg daily) continuously for 28 days followed by a two week rest period. Patients will be 
reassessed with transurethral resection and urine cytology.  Those with residual/recurrent 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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disease will receive a second course identical to the initial protocol.  Those with a complete 
response following initial or second treatment will be placed on maintenance BCG (3 week 
course every 6 months for 2 years).  Those failing (progression, intolerance) 
initial/secondary treatments will be offered alternative therapy.     
1. 
OBJECTIVES 
PRIMARY OBJECTIVE:  
The primary objective of this study is to determine the complete response rate ( (negative bladder 
biopsy, negative urine cytology, normal exam under anesthesia)  at 3 months in high risk non-
invasive urothelial carcinoma of the lower urinary tract (bladder, prostatic urethra) patients treated 
with a 6-week induction course of intravesical bacillus Calmette-Guerin (BCG) followed by a 6 
week course of oral Sunitinib (4 weeks on drug, 2 weeks off).   
SECONDARY OBJECTIVES OF THE TRIAL:   
1. Determine the percentage of patients with high risk non-muscle  invasive urothelial 
carcinoma of the lower urinary tract (bladder, prostatic urethra) with a complete response 
(negative bladder biopsy, negative urine cytology, normal exam under anesthesia) at 6 
months to the study regimen  
2. To assess the recurrence-free survival of patients treated with BCG followed by Sunitinib at 
2 years in patients with an intact bladder. 
3. To determine toxicity related to treatment with BCG followed by Sunitinib.   
Correlative objectives of trial:   
To correlate changes in VEGF, VEGFR, p53, HIF1a and other cytokine expression in the voided urine, 
serum and/or tissue with response in patient treated with BCG followed by Sunitinib  
 
2. 
BACKGROUND 
2.1 
NON-MUSCLE INVASIVE UROTHELIAL CARCINOMA OF THE LOWER URINARY TRACT 
Approximately 67,000 people will be diagnosed with bladder cancer in 2007.[1]  Most patients are 
initially diagnosed with non-muscle invasive bladder cancer.  Non-muscle invasive urothelial cancer 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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of the lower urinary tract is characterized by tumor involving the mucosa or lamina propria of the 
urinary bladder and/or prostatic urethra.  These patients are most commonly treated with initial 
endoscopic resection.  The natural history of non-muscle invasive urothelial carcinoma is one of 
frequent recurrences.  The close surveillance of patients with non-muscle invasive urothelial 
carcinoma with repeated upper tract imaging (computed tomography, intravenous pyelogram), 
office cystoscopy (every 3 months initially), and urine cytology combined with the need for frequent 
return to the operating room for repeat endoscopic resection make bladder cancer one of the most 
expensive malignancies to treat per individual patient.[2]  
This surveillance pattern is driven by the fact that up to 1/3 of patients will progress to more 
invasive disease.  A multitude of both clinical and molecular factors have been studied to attempt to 
identify which patients are at high risk of progression.[3]  To date, the two proven factors associated 
with risk of progression are grade and stage.  Patients with high grade tumors have at least a 50% 
chance of recurrence.  This can range from 50-90% in patients with carcinoma in situ (CIS), a flat 
high grade mucosal lesion.  Both high grade tumors and CIS carry a high risk of progression to 
muscle invasive and/or metastatic disease.  In addition, patients with T1 tumors (invasion into the 
lamina propria) have a 50-70% chance of recurrence and a high probability of progression to more 
invasive disease.[4]  Once a patient has advanced to muscle invasive disease, they have decreased 5-
year survival similar to those patients who present initially with muscle invasive urothelial 
carcinoma.[5]  In addition, the current standard for muscle invasive bladder cancer is radical 
cystectomy with or without neoadjuvant chemotherapy which is associated with a 1-3% peri-
operative mortality ratio, a 20-30% peri-operative complication ratio, and significant alteration in 
the patient’s quality of life.[6, 7] Clinical efforts have focused on the prevention of recurrence and 
progression for patients with non-muscle invasive urothelial carcinoma.   
For those patients with adverse features including tumor recurrence, multifocality, invasion into the 
lamina propria, sessile architecture, mixed histology, high grade tumor, or tumors associated with 
carcinoma in situ, endoscopic resection is typically combined with intravesical therapy.  There are a 
variety of current intravesical agents used in the management of non-muscle invasive bladder cancer.  
Mitomycin is a chemotherapeutic agent that is frequently instilled at the time of endoscopic resection.  
In several series, mitomycin has been shown to reduce the risk of recurrence when combined with 
endoscopic resection.[8]  However, it does not appear to prevent disease progression which is the 
predominant factor in overall survival in this population.  As a consequence several intravesical agents 
are used clinically in the peri-operative period to prevent tumor recurrence and progression.  To date, 
the most effective agent is bacillus Calmette Guerin (BCG).  In several randomized controlled studies in 
patients with non-muscle invasive disease, the average percentage of patients with complete response to 
intravesical chemotherapy was roughly 30% compared to 45-55% for those treated with BCG at 3 
months.  While the percentage of patients responding at 3 months  with CIS is similar to other tumors 
using intravesical chemotherapy, up to 70% of patients treated with BCG will have a complete response 
at 3 months.[9]  An expected 30% of patients failing initial induction with BCG will respond to a second 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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course of BCG.  However, residual disease following two induction courses of BCG denotes a high risk of 
tumor progression.      
2.2 
ANGIOGENESIS AND UROTHELIAL CANCER 
Angiogenesis is a prerequisite to cancer growth and metastasis.  It is regulated by the balance 
between various angiogenic and antiangiogenic factors released by cancer cells or nonmalignant 
cells that infiltrate the cancer [10, 11].    Microvessel density (MVD), a measure of tumor 
angiogenesis, has been shown to correlate with a higher incidence of metastasis and a worse 
prognosis in various cancers, including bladder carcinoma [12, 13]. Specifically, the development of 
new vasculature has been associated with progression of urothelial cancer from superficial to 
muscle invasive disease [14].  Canoglu et al [15] looked at tumor specimens from 77 patients with 
bladder cancer.  They found MVD to correlate with tumor grade, stage and prognosis.  Significantly 
higher MVD was shown in invasive tumors compared to superficial tumors (p < 0.05).  MVD was also 
shown to increase with tumor grade and stage (p < 0.05) and, high MVD was correlated with risk of 
clinical progression in both superficial and invasive bladder carcinomas (p < 0.05, p < 0.001) 
respectively. 
Additional support for angiogenesis in the development and progression of urothelial carcinoma has 
been shown by way of angiogenic factors and their receptors. Tyrosine-kinase receptors, including 
many growth factor receptors such as the receptors for fibroblast growth factor (FGF), epidermal 
growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell 
growth factor (PDGF) and Her2/neu, have been found over expressed in  tissue, serum, and urine of  
patients with bladder cancer [16-18].  For many of these growth factor receptors, the degree of 
expression has been associated with the progression of cancer and a poor prognosis [19].  Several 
investigators have reported  a positive association between over- expression of EGFR and high-
grade, high-stage bladder cancer; identifying the receptor as an independent prognostic factor in 
patients with advanced bladder cancer by some, but not all investigators [20-23].   
Of the angiogenic factors, VEGF has been identified as a crucial regulator of both normal and 
pathologic angiogenesis.  VEGF produces a number of important biologic effects including 
endothelial mitogenesis and migration, extracellular matrix remodeling via induction of proteinases, 
increased vascular permeability and maintenance of newly formed vasculature [24].  VEGF exerts its 
biologic effects through the binding and stimulation of two receptors on the surface of endothelial 
cells: Flt-1 and KDR.  Increased VEGF expression has been measured in most human tumors 
including those of the bladder [25-27].  In addition to the high expression rate, several investigators 
have reported a correlation of VEGF expression to higher stage, progression and prognosis in 
bladder cancers.  With the progression of tumor grade and clinical stage, the positive rate of VEGF 
gene expression significantly increased [26-28].  Serum VEGF levels appear to be significantly 
associated with tumor stage, grade, vascular invasion and carcinoma in situ.  


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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Another angiogenic factor shown to be important in the pathobiology of urothelial cancer is platelet-
derived endothelial cell growth factor (PDGF).  Higher PDGF levels have been associated with more 
invasive and higher grade urothelial carcinoma [29, 30] and appear to predict for recurrence and 
progression [31].  As described in further detail below, the effect of BCG may be related to VEGF 
inihibition; therefore, the addition of sunitinib following BCG may improve the complete response 
rate of patients compared to those receiving BCG alone.      
2.3 
BACILLUS CALMETTE-GUERIN AND UROTHELIAL CARCINOMA 
Molecular Formula and Chemical Name 
 
TICE BCG ((Organon) is an attenuated, live culture preparation of the Bacillus of Calmette and 
Guerin () strain of Mycobacterium bovis.  BCG is grown in a medium consisting of potatoes, 
glycerine, asparagines, citric acid, potassium phosphate, magnesium sulfate, ferric ammonium 
citrate, calcium chloride, copper sulfate, and zinc sulfate.  Monosodium glutamate is added to the 
freeze-dried preparation which is delivered in 50 mg.  Prior to use, the freeze dried preparation is 
reconstituted with the diluent (3 ml) containing sodium chloride, sodium phosphate, and Tween 80.  
A single dose consists of the reconstituted BCG combined with 50 ml of sterile normal saline.   
Clinical Studies  
Pharmacology/Proposed Mechanism of Action 
TICE® BCG induces a granulomatous reaction at the local site of administration.  Intravesical  TICE 
BCG has been used as a therapy for, and prophylaxis against recurrent tumors in patients with 
carcinoma in situ (CIS) of the urinary bladder, and to prevent recurrence of Stage TaT1 papillary 
tumors of the bladder at high risk of recurrence. The precise mechanism of action is unknown.  The 
fundamentally agreed upon mechanism of action  of BCG intravesical therapy for superficial bladder 
cancer is the generation of a non-specific immune response.  It is believed that BCG is internalized by 
both antigen presenting cells and tumor cells.  These antigen presenting cells present BCG antigen to 
T cells and generate a cellular immune response.  These cells produce a wide variety of cytokines 
(IL-2, Il-12, IFNα, IFNγ, etc...) that recruit mononuclear cells (macrophages, natural killer cells, etc…) 
that generate a nonspecific tumor kill.  Beyond the nonspecific killing of tumor cells from the cellular 
immune response, the local production of cytokines may have an anti-angiogenic impact.[32] 
   
Clinical Safety and Efficacy 
 
The estimated response rate for patients with high risk non-invasive disease is approximately 50% 
with patients with isolated carcinoma in situ experiencing response rates of 70%. Based on several 
randomized controlled trials performed by the Southwest Oncology Group in the early 1990s, 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
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compared to endoscopic resection alone as well as intravesical chemotherapy with mitomycin, 
thiotepa, and other agent, BCG demonstrates superior delay in time to recurrence.[33, 34] However, 
delay in recurrence has not definitively translated into a change in overall survival or time to 
progression.[35] 
In an effort to improve the long term effects of BCG, several groups have advocated maintenance 
BCG for those patients who respond to an initial or second induction course.  Results of a 
randomized controlled study of BCG with or without maintenance therapy demonstrated increased 
time to disease recurrence compared to a single induction course (77 versus 36 months, log rank 
test p-value <0.001).[34] 
Intravesical BCG is routinely used in Urologic practice and the safety and side effects are well 
established.  The most frequent side effects of BCG include the development of lower urinary tract 
symptoms during treatment including urgency and frequency.  In addition, patients may develop 
microscopic hematuria during BCG therapy. 
Systemic symptoms may occur with BCG administration including fever, malaise, and fatigue.  The 
most serious side effects related to BCG are infection.  Up to 10 % of patients may develop urinary 
tract infection which is most commonly caused by coliform bacteria.  However, local infection of the 
bladder and prostate may develop which can usually be managed by discontinuation of the BCG and 
treatment with fluoroquinolone antibiotics.  Rare systemic infections related to BCG most commonly 
occur when BCG is delivered to patients with gross hematuria or following traumatic foley 
catheterization.  This is managed by discontinuation of therapy and treatment with anti-tuberculosis 
agents in addition to fluoroquinolone antibiotics.  This systemic infection may require 
hospitalization for management of symptoms and initiation of therapy.   
2.4 
SUNITINIB (SUNITINIB MALATE)  
Molecular Formula and Chemical Name 
Sunitinib (Sunitinib malate) is a small molecule, multi-targeted receptor tyrosine kinase inhibitor 
that selectively targets and intracellularly blocks the signaling pathways of receptor tyrosine kinase 
(RTKs).  The free base has a molecular weight of 398.48 and the L-malate salt, the form used in 
clinical trials. Figure 1), has a molecular weight of 532.57.  The chemical name of the L-malate salt is 
5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethylpyrrole-3-carboxylic acid (2-
diethylamino-ethyl)-amide, compound with (S)-2-hydroxy-succinic acid 1:1. 
Figure 1. The Structural Formula of Sunitinib 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
13 
 
N
H
F
N
H
N
H
N
O
O
HOOC
COOH
OH
H
.
 
Sunitinib drug substance has been identified by NMR spectroscopy as the (Z)-isomer.   
Clinical Studies 
Pharmacokinetics 
Single- and multiple-dose clinical pharmacokinetic studies of Sunitinib over a range of 25 to 100 mg 
daily have been performed.  Regimens have included either a repeated 4-week cycle comprising 
daily treatment for 2 weeks followed by a 2-week rest period (Schedule 2/2) or a repeated 6-week 
cycle comprising daily treatment for 4 weeks followed by a 2-week rest period (Schedule 4/2).  The 
Cmax and AUC of SU0112498 increase in proportion to dose across the range of doses studied.  No 
dose-dependent changes in tmax or t1/2 have been observed.  Sunitinib is metabolized primarily by 
the cytochrome P450 enzyme, CYP3A4, to produce the active N-desethyl metabolite, SU012662.  To 
date, no other major metabolite has been identified.  The terminal elimination half-life of Sunitinib 
and SU012662 are approximately 40 hours and 80 hours, respectively.  Trough plasma drug 
concentrations plateau during the first 2 weeks of dosing.  Accumulation across multiple cycles of 
treatment has not been observed.  Sunitinib may be administered without regard to meals. 
 
Clinical Safety and Efficacy 
To date, over 1500 patients with advanced malignancies have been treated with Sunitinib.  Multiple 
phase 1, 2 and 3 studies have been conducted or are underway.  The primary dose limiting toxicity in 
phase 1 studies was fatigue/asthenia, which generally occurred 10 to 15 days after start of daily 
therapy, and was readily reversible upon discontinuation of Sunitinib treatment.  Overall, the most 
frequent adverse events associated with Sunitinib treatment have been constitutional symptoms 
(fatigue/asthenia), gastrointestinal effects (nausea, diarrhea, stomatitis, dyspepsia), 
myelosuppression (eg, neutropenia, thrombocytopenia), and dermatologic effects (e.g., dermatitis, 
skin discoloration, hair depigmentation).  Clinically significant neutropenia has been observed in 
very few solid tumor patients and febrile neutropenia has rarely been observed in this patient 
population.  The degree of adverse event severity has correlated with higher drug exposure and/or 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
14 
 
lower patient performance status for both patients treated with previous chemotherapy and 
chemotherapy-naïve patients.   
In studies evaluating starting doses that ranged from 75 to 100 mg daily, cardiac hypokinesis and 
clinical signs of congestive heart failure were reported in 4 of 62 advanced acute myeloid leukemia 
patients.  The relationship to Sunitinib exposure was confounded by disease morbidities and prior 
anthracycline exposure.  At the 50-mg dose level, asymptomatic decreases in cardiac ejection 
fraction have been observed in <3% of solid tumor patients, either with or without a prior history of 
cardiovascular disease or anthracycline exposure.   
The maximum tolerated dose of Sunitinib using the Schedule 4/2 has been defined as 50 mg in Phase 
1 clinical studies in patients with advanced solid tumors.  Patients receiving this dose of  Sunitinib 
achieved target steady state plasma concentrations of Sunitinib malate plus SU012662 of greater 
than 50 ng/mL. 
Clinically relevant Sunitinib antitumor activity has been demonstrated in Phase 1 patients with 
advanced malignancies, including individuals with renal cell carcinoma, gastrointestinal stromal 
tumor, neuroendocrine tumor, sarcoma, thyroid cancer, melanoma and non-small cell lung cancer 
(NSCLC).  The greatest clinical experience with Sunitinib is in solid organ malignancies including 
metastatic renal cell carcinoma and gastrointestinal stromal tumors.  Results of phase II and III 
studies in this patient population has demonstrated progression free survival ranging from 30.4 to 
47.3 weeks and objective response rates from 22 to 48%.  In addition, a phase 2 study pivotal study 
of Sunitinib in patients with cytokine-refractory metastatic renal cell carcinoma demonstrated a 
response rate of approximately 40% with a TTP of greater than 8 months compared to historical 
experience of less than 10% and 3 months respectively. Recent data suggests that sunitinib does 
improve progression free survival in patients with metastatic renal cell carcinoma compared to IFN 
in a phase III randomized controlled study involving 750 patients.  Numerous phase II and III studies 
in patients with imatinib resistant gastrointestinal stromal tumors (GIST) have demonstrated 
median progression free survival of 32 weeks (95% confidence interval 25-48) and median overall 
survival estimated at 88 weeks (95% CI   Sunitinib has been or is currently being evaluated in 
multiple other solid organ tumor settings including neuroendocrine tumors, breast cancer, lung 
cancer, colorectal cancer, gastric cancer, hepatocellular cancer, prostate cancer, and metastatic 
bladder cancer. 
   
2.5 
RATIONALE 
Despite a complete response of 45-55% in patients with non-muscle invasive urothelial carcinoma 
involving the lower urinary tract at 3 months, many patients suffer from multiple recurrences and 
progression in up to 1/3 of patients.  In fact, there is little evidence demonstrating that BCG therapy 
prevents disease progression and the underlying hope of the therapy is that a delay in recurrence will 
translate into death from competing causes in this population before progression can occur.  While 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
15 
 
radical cystectomy is an effective local therapy for patients with high risk non-invasive disease, roughly 
15% of patients will still develop progression.[36]  More importantly, the morbidity of radical 
cystectomy as described above represents a barrier to treatment in some individuals.  Thus, there is a 
real need to identify newer therapies that reduce morbidity and improve outcomes in patients with non-
invasive urothelial cancer.  While multiple drug regimens have been the standard for many forms of 
cancer including invasive bladder cancer, few reports exist on multidrug regimens for non-invasive 
bladder cancer.  BCG combined with intravesical interferon alpha is the most commonly used multidrug 
regimen for patients failing standard BCG therapy.  This regimen likely allows dose reduction of BCG 
without significant gains over BCG therapy alone.[37]    
The fundamentally agreed upon mechanism of action of BCG intravesical therapy for superficial 
bladder cancer is the generation of a non-specific immune response.  It is believed that BCG is 
internalized by both antigen presenting cells and tumor cells.  These antigen presenting cells present 
BCG antigen to T cells and generate a cellular immune response.  These cells produce a wide variety 
of cytokines (IL-2, Il-12, IFNα, IFNγ, etc...) that recruit mononuclear cells (macrophages, natural 
killer cells, other inflammatory cells) that generate a nonspecific tumor kill.  Beyond the nonspecific 
killing of tumor cells from the cellular immune response, the local production of cytokines may have 
an anti-angiogenic impact.[32] 
Overexpression of vascular endothelial growth factors (VEGF) is well described in invasive as well as 
superficial bladder cancer.[27]  It has also been demonstrated that p53 abnormalities (very common 
in aggressive bladder cancer) can result in increased VEGF expression due to failure of regulation of 
p53 as a transcription factor.[38]  IFNα has been shown to down regulate VEGF expression.  As a 
consequence, the production of cytokines (specifically IFN) indirectly generated by  BCG treatment 
may target a critical pathway in which superficial bladder cancer becomes invasive.[39]   This 
mechanism of tumor progression has been targeted clinically by combining BCG and interferon 
intravesically for BCG failures.  While the results of this data are mixed, the addition of IFN does 
allow for similar clinical results with the reduction of BCG dose further strengthening the concept of 
the role of IFN in BCG effectiveness.   
Recent reports demonstrate clinical response in patients with metastatic bladder cancer treated 
with sunitinib after recurrence following standard chemotherapeutic regimens.[40]  The addition of 
sunitinib following BCG in order to consolidate VEGF inhibition may result in superior 3 month 
complete response rates.  We know that patients who have a complete response to BCG at 3 months 
have improved disease control and an attempt to improve the complete response rate in this early 
phase may improve recurrence free survival in this population.   
2.6 
CORRELATIVE STUDIES BACKGROUND 
Multiple clinical trials are attempting to either understand the role of cytokines in the response to 
BCG and/or combine BCG with systemic agents to provide a multidrug regimen to target this 
disease.  These studies are including urine based markers which may allow a better prediction of 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
16 
 
who will respond to BCG and patients more likely to fail BCG therapy.  However, to date visual 
inspection with cystoscopy combined with biopsy is the standard method to detect response to BCG. 
 Identification of a marker to predict or assess response would allow clinicians to guide patients 
toward intravesical therapy versus more aggressive forms of therapy in the case where BCG was not 
likely to have an effect.      
The only current multi-drug regimen with clinical data is BCG combined with IFN.  The rational as 
outlined above for this regimen is that both treatments have downstream effect on VEGF inhibition.  
Recent evidence shows that VEGF expression is prominent in the bladder urothelium and may be 
altered by inflammation. [46] However, there have been mixed results of BCG + IFN with the 
addition of IFN allowing a reduction in BCG dose with a similar outcome to BCG alone.  A potentially 
more powerful combination could be following BCG therapy with Sunitinib for a synergistic 
blockade of the VEGF pathway as VEGF is a well recognize target of Sunitinib.[41, 42]   
As described above, VEGF inhibition is likely important in BCG’s effect on bladder cancer.  VEGF 
receptors are present in the normal urothelium and are also upregulated during inflammation such 
as that occurring in interstitial cystitis.  BCG is known to cause bladder inflammation and therefore 
may cause upregulation of VEGFR receptors in normal as well as malignant bladder cells.[27]  Thus 
the combination of BCG followed by sunitinib may sensitize bladder tumors to respond to BCG by 
blocking the VEGF receptor pathway.  Alternatively, tumor cells not affected by BCG may be targeted 
by sunitinib thus providing an opportunity to consolidate complete response to therapy.   
Additionally, other tissue markers may provide important information for patient stratification.  For 
example, p53 mutation, which is common even in non-muscle invasive bladder cancer [32],  may 
also be involved in regulated angiogenesis and response to hypoxia [33]  Thus, the p53 status of 
patients may alter responses to sunitinib.    Another important tissue marker is HIF1a, a marker 
upregulated with tissue hypoxia.  Elevated tissue levels of HIF1a may indicate activation of the VEGF 
pathway, and thus indicate patients who would be more likely to respond to treatment [35]  Each of 
these additional hypotheses can be tested using formalin-fixed, paraffin-embedded tissues subjected 
to immunoperoxidase staining after antigen retrieval [ 34].   
Urine represents an ideal medium to evaluate response to therapy in patients with localized bladder 
cancer as it may directly indicate the response to therapy.  .  We will investigate the effect of BCG and 
sunitinib therapy on urinary VEGF and VEGFR levels. Additionally, As there are no known 
biomarkers of response to therapy of non-muscle invasive bladder cancer to BCG and/or sunitinib 
we will utilize urine, serum and tissue obtained in this study to identify potential biomarkers that 
may be predictive of response to treatment,  
3. 
PATIENT SELECTION 


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17 
 
3.1 
 
INCLUSION CRITERIA 
3.1.1. Patients must have histologically confirmed urothelial carcinoma confined to the 
urinary bladder and/or prostatic urethra by bladder biopsy within 6 weeks of study 
enrollment.  
• 
Patients are eligible if there biopsy was done within 3 months of enrollment and a 
cystoscopy demonstrates no gross disease within 6 weeks of enrollment.     
3.1.2. Tumor histology with >50% transitional cell carcinoma histology 
3.1.3. Tumor stage ≤ T1 confirmed by pathology report 
• 
Patients with a T1 tumor will require a restaging TURBT confirming no higher stage 
tumor prior to study enrollment 
3.1.4. High grade tumor as defined by the WHO/ISUP 1998 classification system. (Presence 
of carcinoma in situ constitutes a high grade tumor) 
3.1.5. No BCG within 12 months of enrollment 
• 
Patients are allowed to have received a single dose of intravesical chemotherapy 
(excluding BCG) in the operating room following transurethral resection 
documenting non-muscle invasive urothelial carcinoma of the lower urinary tract. 
• 
Patients are allowed to have received a previous 6 week cycle of any standard 
intravesical chemotherapy if > 3 months prior to enrollment.   
3.1.6. Age >18 years.   
3.1.7. ECOG performance status 0 or 1 (see Appendix A) 
3.1.8. Patients must have adequate organ and marrow function as defined below: 
 
 
 
 
 
 
3.1.9. Timing guideline for pre-study labs and measurements: 
• 
All pre-study labs required for determination of eligibility are to be completed 
within 6 weeks prior to registration. 
• 
X-rays and/or scans to determine disease status are to be completed within 6 
months prior to registration (or the next business day if falls on a weekend or 
holiday). 
3.1.10. All patients must be informed of the investigational nature of this study and must 
sign an informed consent in accordance with institutional and federal guidelines. 
X   absolute neutrophil count 
>1,500/mcL 
                X   Platelets 
>100,000/mcL 
                X   total bilirubin 
≤ 1.5 upper limit of  
                X   AST(SGOT)/ALT(SGPT) 
≤2.5 X institutional upper 
limit of normal 
                X   Serum creatinine 
< 2.0 mg/dl  
                X   MUGA scan 
within institutional normal 
limits 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
2 
 
3.2 
 
EXCLUSION CRITERIA 
3.2.1. Patients with a prior history of radiation for bladder cancer 
• 
Patients with a prior history of radiation for prostate cancer are eligible for the study 
3.2.2. ≥ T2N0M0 transitional cell carcinoma of the bladder on current pathology or in the 
past. Patients with a prior history of upper tract urothelial carcinoma are eligible for 
participation in the study as long as there is no evidence of disease for 6 months 
prior to study enrollment 
3.2.3. Patients with other malignancies are eligible for enrollment in the study but should 
not be on active treatment for this malignancy within 12 months of study enrollment. 
 Patients with prior history of local treatment for prostate cancer are eligible for 
participation in the study 
3.2.4. Patients cannot have received Sunitinib or other anti-angiogenic therapy for at least 
12 months prior to enrollment in the study 
3.2.5. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to BCG and Sunitinib 
• 
Patients with prior systemic infection with  BCG are not eligible for the study 
• 
Patients with prior intolerance to BCG may be considered  
3.2.6. Major incisional surgery within 4 weeks of study enrollment 
3.2.7. Bleeding diathesis or unresolved gross hematuria after bladder biopsy 
3.2.8. Known HIV – positive patients may not participate.  This is to avoid additional 
complications that immune suppression and HIV infection may cause due to 
treatment with BCG, which is a live attenuated bacteria that is known to cause 
systemic infection in patients who are immunocompromised. 
3.2.9. Patients taking agents that result in immunosuppresion are not eligible for the study 
due to the potential for the increased risk of systemic infection in those patients 
receiving BCG 
3.2.10. Any of the following within the 6 months prior to study drug administration:  
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure (CHF), cerebrovascular accident or 
transient ischemic attack, or pulmonary embolism. 
3.2.11. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2. 
3.2.12. Patients with history of or who are suspected to have CHF can be included as long as 
they are asymptomatic and have an ejection fraction that is equal to or above the 
institutional lower limit of normal by baseline MUGA (obtained within 28 days of 
registration or the next business day if falls on a weekend or holiday).  
3.2.13. QTc interval > 500 msec on baseline EKG (to be done within 6 weeks prior to 
registration or the next business day if falls on a weekend or holiday). 
3.2.14. Hypertension that cannot be controlled by medications (>150/100 mm Hg despite 
optimal medical therapy).   


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
3 
 
3.2.15. Patient may not have unresolved bacterial infection. 
3.2.16. Patients with hypothyroidism that cannot be adequately controlled with medication 
will be excluded.  All patients will be monitored at trial initiation with a TSH.   
3.2.17. Concurrent treatment on another clinical trial.  Supportive care trials or non-
treatment trials, e.g. QOL, are allowed. 
3.2.18. Pregnancy or breastfeeding.  Female subjects must be surgically sterile or be 
postmenopausal, or must agree to use effective contraception during the period of 
therapy.  All female subjects with reproductive potential must have a negative 
pregnancy test (serum or urine) prior to enrollment.  Male subjects must be 
surgically sterile or must agree to use effective contraception during the period of 
therapy.  The definition of effective contraception will be based on the judgment of 
the principal investigator or a designated associate.    
3.2.19. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and in 
the judgment of the investigator would make the subject inappropriate for entry into 
this study. 
3.3 
INCLUSION OF WOMEN AND MINORITIES 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
4.0 PRETREATMENT EVALUATION 
Pre-enrollment screening tests and evaluations will be used to determine the eligibility of each 
candidate for study inclusion.  All enrollment evaluations must be assessed within the interval 
specified prior to treatment.  All dates are specified below but may occur on the following day if it 
falls on a weekend or holiday.  
 
4.1 
CLINICAL:   (within 6 weeks prior to registration) 
4.1.1Complete history and physical examination. 
4.1.2Height, weight, and ECOG Performance Status. 
4.1.3Baseline evaluation of symptoms and medications.  Patients medication list will be 
reviewed and compared to the list in Appendix F.  Medication adjustment will be performed 
to eliminate the possibility of interaction with Sunitinib.  
  
4.2 
LABORATORY:   (within 6 weeks prior to registration) 
4.2.1Hematology:  Complete blood count, differential and platelet count. 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
4 
 
4.2.2Comprehensive panel: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, AST, ALT, alkaline phosphatase, bilirubin, total protein and albumin. 
4.2.3TSH 
4.2.4Urine cytology 
 
 
4.3 IMAGING AND DIAGNOSTIC STUDIES: (within 6 months prior to registration) 
4.3.1Computed tomography scan (with contrast), intravenous pyelogram, or magnetic 
resonance imaging of the abdomen and pelvis.  
4.3.2A non-contrasted CT combined with renal/bladder ultrasound can be obtained for those 
patients with a contra-indication to CT and/or MRI  
4.4 
ELECTROCARDIOGRAM. (within 3 months of registration) 
4.5 
MUGA SCAN (within 6 weeks of study enrollment) 
5.0 REGISTRATION PROCEDURES 
5.1 
GENERAL GUIDELINES 
Eligible patients will be recruited from the University of Michigan, Department of Urology Clinics.  
Patients signing informed consent and meeting eligibility criteria will be registered on study by the 
Study Coordinator.  Once registration is complete, the registrar will provide the registering 
individual a study subject identification number.   
Following registration, patients should begin protocol treatment within 3 weeks.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.   
 
6. 0 TREATMENT PLAN (Treatment must begin within 6 weeks after registration) 
6.1 
BCG 
6.1.1 DOSE LEVELS: Dose Levels for  TICE BCG 
Dose Levels for TICE BCG 
Dose Level  
Weekly Dose/ Route 
Dispensed As  
Schedule 
Starting dose level:  0  
 50 mg reconstituted in 50 ml normal 
saline/intravesical 
vial  
1day/week x 6 weeks 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
5 
 
               –1  
 25 mg reconstituted in 50 ml normal 
saline/intravesical 
½ vial 
1day/week x 6 weeks 
              –2  
12.5 mg reconstituted in 50 ml normal 
saline/intravesical 
¼ vial 
1day/week x 6 weeks 
6.1.2 BCG ADMINISTRATION 
• 
Patients will undergo urinalysis in clinic and the decision to proceed with BCG therapy will 
be based on standard clinic procedures (Appendix B). 
• 
BCG is delivered via a 12-16 French Red Robinson catheter by a clinical nurse.  Patients are 
encouraged to decrease fluid intake for up to 6 hours prior to administration.  BCG is 
retained in the urinary bladder for two hours following administration.  Patients are 
requested to void sitting down to avoid contamination and requested to disinfect the toilet 
with bleach after as well as for any voids up to 6 hours after treatment.    
• 
Study drug  TICE BCG will be administered by a nurse in clinic as  50 mg reconstituted in 50 
ml sterile normal saline 1 time/week for a total of 6 weeks.  Patients without a complete 
response after the initial cycle will be offered a second identical cycle.   
• 
The Study drug dose may be adjusted according to individual patient tolerance as outlined 
below in section 10.  The BCG can be diluted in ½ to ¼ the original dose.  
• 
Induction and/or maintenance BCG may be administered by a local urologist at the approval 
of the principal investigator 
o Induction BCG protocol by local urologist will be verified by the principal 
investigator to ensure compliance with study protocol 
o Maintenance BCG will be administered following the study calendar. 
 
Deviations to the maintenance BCG schedule will be reported to the study 
coordinator along with reason.  Ultimately, the administration of 
maintenance BCG and its timing are at the discretion of the treating 
physician.    
 
Records will be obtained from the local urologist to document dose, dates of 
administration and completion of course for a length of 2 years following 
completion of induction course of BCG. 
6.1.3 CONCOMITANT MEDICATION(S) 
Intravesical BCG is not metabolized.  Because BCG works by stimulating the immune system, 
patients on immunosuppressive agents (corticosteroids) or immunocompromised (HIV infection, 
transplant patients on immunosuppressive regimens) should not be given BCG.  In addition, 
antimicrobial therapy should be avoided during BCG administration due to the potential 
antimicrobial effect on the BCG itself.  (PLEASE REFER TO CONCOMINANT MEDICATION SECTION 
IN REGARD TO SUNITINIB) 
6.1.4 DOSE REDUCTIONS: Please refer to Section 11. 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
6 
 
6.1.5 SUPPORTIVE CARE GUIDELINES: 
• 
Irritative bladder symptoms occur in 50% of patients 
o For patients with bothersome symptoms, medications such as pyridium, 
propantheline bromide, oxybutynin and acetaminophen can be used 
• 
“Flu-like” symptoms (malaise, fever, chills) 
o Are related to the immune and hypersensitivity response and can be managed with 
ibuprofen, acetaminophen, and antihistamines 
• 
Occular symptoms (uveitis, conjunctivitis, iritis, keratitis, granulomatous choreoretinitis) 
alone or in combination with joint symptoms (arthritis, arthralgia), urinary symptoms, 
and/or skin rash have been reported.  Patients positive for HLA-B27 appear to be at elevated 
risk 
o Dose reduction will be attempted 
o If persistent, BCG will be halted although patients will be allowed to continue to the 
Sunitinib portion of the study.   
• 
Infection:  Urinary tract infection, prostatitis, orchitis/epidydimitis have all rarely been 
reported with BCG.  Serious disseminated infections to the lung, liver, bone, bone marrow, 
kidney, and regional lymph nodes have been reported in case reports in the literature.  
Finally, sepsis has been reported with associated mortality.   
• 
If a patient develops persistent fever (> 38.5 C) or experiences an acute febrile illness 
consistent with BCG infection, BCG will be immediately discontinued and the patient will be 
evaluated for BCG infection 
• 
Local infections may often be managed with discontinuation combined with a 
fluoroquinolone antibiotic such as ciprofloxacin or levofloxacin.  However, rare cases of 
epidydimitis and orchitis have not been successfully managed and may require 
antituberculosis therapy and/or orchiectomy 
• 
More serious infections will be evaluated and might require one of the following actions: 
o Hospital admission with urine and blood cultures 
o Supportive therapy 
o Infectious disease physician consultation 
o Initiation of anti-tuberculosis therapy including isoniazid, rifampin, and/or 
ethambutol (not pyrazinimide) 
 
6.2 
SUNITINIB (Treatment with Sunitinib will occur according to the study calendar) 
6.2.1 DOSE LEVELS: Dose Levels for Sunitinib 
Dose Level  
Daily Dose/ Route 
Dispensed As  
Schedule 
Starting dose level:  0  
50 mg, PO 
1 x 50-mg capsules  
4 weeks on and 2 
weeks off, Q 6 weeks 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
7 
 
               –1  
37.5 mg, PO 
1 x25 mg capsule 
and 1x 12.5 mg 
capsule   
4 weeks on and 2 
weeks off, Q 6 weeks 
              –2  
25 mg, PO 
1 x 25-mg capsules  
4 weeks on and 2 
weeks off, Q 6 weeks 
6.2.2 SUNITINIB ADMINISTRATION  
• 
Study drug (Sunitinib) will be given at 50 mg/day as a single agent for 4 consecutive weeks 
followed by a 2-week rest period to form a complete cycle of 6 weeks. Study drug will be 
orally self administered once daily without regard to meals. 
• 
The Study drug dose may be adjusted according to individual patient tolerance as outlined 
below in section 10.   
• 
Patients must be provided with a diary to document compliance, (Appendix C). 
• 
Patients will be required to return all bottles of study medication at the beginning of each 
cycle.  The number of capsules remaining will be documented and recorded. 
6.2.3 CONCOMITANT MEDICATION(S) 
Sunitinib is metabolized primarily by liver enzymes, in particular CYP3A4.     Caution is 
recommended when administering study drug with inhibitors or inducers of the CYP3A4 family (see 
appendix G). 
6.2.4 DOSE REDUCTIONS: Please refer to Section 11. 
6.2.5  SUPPORTIVE CARE GUIDELINES: 
• 
Diarrhea 
o Lomotil or Imodium may be used by patients developing diarrhea during treatment. 
• 
Hypertension 
o Blood pressure should be well controlled before starting study drug. 
o Standard blood pressure medications should be used for patients that develop 
hypertension during treatment.  
o Diltiazem and verapamil should be avoided if possible as they are potential inhibitors 
of the CYP3A4 pathway (see section 6.2.3). 
o If hypertension develops or worsens while on study drug, treatment should first be 
with optimizing standard anti-hypertensive agents.  If refractory, study drug dose 
modifications can be made.  
o In cases of severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) 
temporary suspension of study drug is recommended until hypertension is 
controlled. 
• 
Fatigue  
o For intolerable fatigue, the next cycle of treatment may be delayed by one week. 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
8 
 
7.0   DURATION OF THERAPY 
7.1 
BCG 
• 
Patients will receive within either 6 weeks of bladder biopsy or within 3 months of bladder 
biopsy and a cystoscopy within 6 weeks of enrollment confirming no visible tumor a 6 week 
course of BCG as described above.   
• 
Please see section 10 for dosing delays and modifications.  Patients unable to complete an 
induction course of BCG will be removed from the study and replaced with a new subject.  
The removed subject will be offered alternative treatment options.   
• 
After completion of a 6 week course of BCG, patients will undergo a 2 week rest period 
before initiating sunitinib 
• 
All patients will be assessed at 3 months after enrollment with repeat bladder biopsy done at 
the study institution and urine cytology regardless of completion of the study drugs as this is 
standard of care.    
• 
Patients demonstrating residual disease at 3 months will receive a second complete cycle of 
the study drugs (BCG followed by sunitinib) if the tumor remains non-muscle invasive.  
However, patients may elect to proceed to alternative treatments if there is residual non-
muscle invasive disease.  Patients completing at least one cycle of the study treatment will be 
assessed for primary and secondary endpoints where applicable.   
• 
Patients with evidence of muscle invasive disease on restaging bladder tumor biopsy will be 
withdrawn from the study and offered standard alternative treatment options.  
• 
Any patients with a complete response to BCG followed by sunitinib at 3 months or 6 months 
will be placed on maintenance BCG therapy which is the current standard of care.  The 
maintenance BCG schedule is outlined in Calendar 2.  Calendar 2 represents an idealized 
version of maintenance therapy and actual maintenance therapy varies according to 
individual physician practice pattern.  As such, we will recommend that patients follow the 
study calendar but the actual administration will be at the discretion of the treating 
physician based on practice pattern and medical decision making.  In addition, surveillance 
cystoscopy and history and physical is dictated by maintenance schedule and will ultimately 
be at the discretion of the treating physician.  Records of each maintenance treatment (dose, 
timing, and delays), surveillance, cystoscopy, history and physical, urine studies, imaging, 
and pathologic data (if obtained) will be collected by the study coordinator and documented 
for a total of 2 years following completion of the initial or second induction course of BCG to 
assess for treatment response.  Please see section 10 for dose modification and reduction.   
7.2 
SUNITINIB 
• 
Patients will receive a single 6 week cycle of sunitinib 2 weeks following a 6 week course of 
intravesical BCG.  Complete responders as determined by no cancer on endoscopic biopsy 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
9 
 
AND no evidence of cancer on urine cytology will be placed on maintenance BCG by their 
treating physician as described in the study calendar.  
• 
Patients with residual disease will receive a second course of treatment identical to the first 
cycle (BCG followed by sunitinib) assuming a normal MUGA scan (see study calendar).   
• 
Patients demonstrating evidence of objective progression by endoscopic biopsy will offered 
alternative treatments 
8.0 CRITERIA FOR REMOVAL FROM STUDY:  
 
8.1Protocol therapy will be discontinued and patients will be removed from study based on any 
of the following criteria (Patients clinical course will be followed for two years.):  
• 
Patients wishes. 
• 
Disease progression as documented by 3 month or 6 month bladder tumor biopsy 
documenting progression to muscle invasive bladder cancer. 
• 
Clinician and patient determine that alternative treatment plan should be pursued.  Reason 
for pursuing alternative therapy will be documented. 
• 
Intercurrent illness that prevents further administration of treatment. 
• 
Unacceptable adverse event(s) that may or may not be directly related to BCG and/or 
sunitinib but that in the judgment of the treating physician make it dangerous for the patient 
to be retreated. 
• 
General or specific changes in the patient’s condition that render the patient unacceptable 
for further treatment in the judgment of the investigator. 
8.2As an excessive rate of withdrawals can render the study un-interpretable, unnecessary 
withdrawal of patients should be avoided. 
8.3When a patient discontinues treatment early, the Investigator will make every effort to 
contact the patient and to perform a final evaluation.  The reason(s) for withdrawal will also be 
recorded.   The reason for terminating therapy should be clearly recorded.   
9.0 DURATION OF FOLLOW-UP  
• 
Patients will be followed by study calendar 
• 
the clinical course of all patients will be followed for a total of 2 years following completion 
of 1st or 2nd induction course of the study therapy.   
10.0 DOSING DELAYS/DOSE MODIFICATIONS 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
10 
 
10.1 TICE BCG 
10.1.1 
DELAYS 
• 
For patients experiencing bladder related symptoms, all attempts will be used to supportive 
care to have the patient complete a complete 6 week course at the full dose.   
• 
Patients with gross hematuria and/or evidence of urinary tract infection during treatment as 
documented by urinalysis and/or confirmed by urine culture will be delayed administration 
of the dose by 1 week and restarted after confirming absence of gross hematuria and/or lack 
of nitrite positivity on dipstick urinalysis.   
• 
Those patients with a greater than 3 week delay between doses during the 1st induction 
course will be removed from the study prior to initiation of sunitinib and be replaced with 
another eligible patient.   Those unable to complete a 2nd induction course of BCG will be 
offered alternative therapy and followed for secondary endpoints where applicable.   
• 
Any patient with systemic infection caused by  TICE BCG will be withdrawn from 
further BCG treatment.  If this occurs during the first induction course, these subjects 
will be replaced, otherwise, patients will be offered alternative therapy and followed for 
applicable secondary endpoints.   
• 
Patients on maintenance BCG therapy will be given the full dose unless persistent 
urinary symptoms or systemic side effects (malaise, fever, fatigue) deter treatment.  
Dose reduction to -1 will be attempted first.  Patients will be allowed to decrease dose to 
-2 if intolerance persists.  Those patients who do not tolerate a dose of -2 during (see 
table in section 6.1). maintenance therapy will be withdrawn from further BCG 
administration and offered alternative treatment plan at the discretion of the treating 
clinician.  
10.1.2 
REDUCTION 
• 
Intrapatient dose reduction by 1, and if needed 2- dose level(s) will be allowed (see Table 
below) depending on the type and severity of toxicity encountered provided that criteria for 
patient withdrawal from study treatment have not been met. 
• 
All intra-patient dose reductions are relative to the lowest dose level of the current cycle. 
• 
No more than 2 dose reductions are permitted in any patient. If further dose reduction is 
required, the patient must be removed from further BCG administration. 
• 
The dosing period may be extended for BCG as outlined in section above 
• 
The below table describes the recommended dose modifications for study treatment 
associated toxicity. 
 
TABLE: DOSE MODIFICATION FOR BCG BASED ON TOXICITY AND GRADE 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
11 
 
* treatment is based on type of infection 
#  if BCG infection of grade 3 or 4 occurs during the 1st induction course, patients will be withdrawn from the 
study and replaced.  Otherwise, patients will be offered alternative therapy at the discretion of the treating 
clinician and followed for appropriate endpoints.    
 
10.2 SUNITINIB:  In the event of any (CTC version 3) drug related grade 3 or 4 non-hematologic or 
grade 4 hematologic adverse event(s) drug should be held until the toxicity resolves to < grade 1 
and then the drug should be restarted at -1 dose level (see 6.1).  
 
10.2.1 DOSE REDUCTION FOR SUNITINIB 
• 
Intrapatient dose reduction by 1, and if needed 2- dose level(s) will be allowed (see 6.1) 
depending on the type and severity of toxicity encountered provided that criteria for patient 
withdrawal from study treatment have not been met. 
• 
All intra-patient dose reductions are relative to the lowest dose level of the current cycle. 
• 
Recovery to acceptable levels of toxicity must occur within 4 weeks to allow continuation in 
the study. 
Toxicity  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Irritative Bladder 
symptoms 
Continue at the 
same dose 
level 
Continue at the same dose level. 
Dose reduction to -1.  If 
Grade 3 toxicity 
persists, reduction to -2. 
 Discontinuation will 
occur at the discretion 
of the treating clinician. 
  
Dose reduction to -1.  If 
Grade 4 toxicity 
persists, reduction to -
2.  Discontinuation will 
occur at the discretion 
of the treating clinician. 
  
Fever, chills and “flu-
like” symptoms 
Continue at 
same dose 
level. 
Continue at same dose level.  
Dose reduction to -1.  If 
Grade 3 toxicity 
persists, reduction to -2. 
 Discontinuation will 
occur at the discretion 
of the treating clinician 
Dose reduction to -1.  If 
Grade 4 toxicity 
persists, reduction to -
2.  Discontinuation will 
occur at the discretion 
of the treating clinician 
Occular symptoms +/- 
joint symptoms 
Continue at the 
same dose 
level. 
Continue at the same dose level. 
Dose reduction to -1.  If 
Grade 3 toxicity 
persists, reduction to -2. 
 Discontinuation will 
occur at the discretion 
of the treating clinician 
Dose reduction to -1.  If 
Grade 4 toxicity 
persists, reduction to -
2.  Discontinuation will 
occur at the discretion 
of the treating clinician 
Infection 
Treat* and 
continue at 
same dose 
after 
resolution of 
symptoms 
within 2 weeks 
Treat* and continue at same dose after 
resolution of infection within 2 weeks  
Withdraw BCG 
treatment# 
Withdraw BCG 
treatment# 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
12 
 
• 
No more than 2 dose reductions are permitted in any patient. If further dose reductions are 
required, patients will discontinue sunitinib therapy. They will continue to be followed per 
protocol.  
• 
The following table describes the recommended dose modifications for study treatment 
associated toxicity. 
TABLE: DOSE MODIFICATION OF SUNITINIB BASED ON TOXICITY AND GRADE 
Recurring grade 3 toxicity requires dose reduction * Patients who develop grade 3 or 4 hyperlipasemia or hyperamylasemia without 
clinical or other evidence of pancreatitis, or grade 4 hyperuricemia or grade 3 hypophosphatemia without clinical symptoms may continue 
study treatment without interruption. *** Patients with recurrent grade 3 lymphopenia and anemia do not require dose modification.  
Recurring grade 4 neutropenia or grade  > 3thrombocytopenia persisting for at least 5 days requires dose reduction in the next cycle.  
Grade 4 lymphopenia does not require dose reduction. 
Management of cardiac ejection fraction.  
Toxicity  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Non-hematologic 
Continue at the 
same dose level 
Continue at the same dose level. 
Withhold dose until 
toxicity is grade ≤1, or has 
returned to baseline, then 
resume treatment at the 
same dose level or reduce 
the dose by 1 level at the 
discretion of the 
investigator* . 
Withhold dose until 
toxicity is grade ≤1, or has 
returned to baseline, then 
reduce the dose by1 level 
and resume treatment, or 
discontinue at the 
discretion of the 
investigator*. 
cardiac toxicity:  
 
Continue at the 
same dose level. 
Continue at the same dose level 
except in the event of• Non-urgent 
ventricular paroxysmal dysrhythmia 
requiring intervention, Withhold 
dose until toxicity is grade ≤1, then 
reduce dose by 1 level and resume 
treatment.   
Remove from further 
therapy, follow for 
applicable endpoints 
Remove from further 
therapy, follow for 
applicable endpoints 
Neurotoxicity 
Continue at the 
same dose level. 
Withhold dose until toxicity is grade 
≤1, then continue at same dose level. 
Withhold dose until 
toxicity is grade ≤1, then 
reduce the dose by 1 level 
and resume treatment. 
Remove from further 
therapy, follow for 
applicable endpoints 
Fever, chills and “flu-
like” symptoms 
Continue at same 
dose level. 
Continue at same dose level.  
Withhold dose until 
toxicity is grade ≤2, or has 
returned to baseline, then 
resume treatment at the 
same dose level. 
Withhold dose until 
toxicity is grade ≤2, then 
reduce the dose by 1 level 
and resume treatment. 
Hematologic  
Continue at the 
same dose level. 
Continue at the same dose level. 
Withhold dose until 
toxicity is grade ≤2, or has 
returned to baseline, then 
resume treatment at the 
same dose***.  
Withhold dose until 
toxicity is grade ≤2, then 
reduce the dose by 1 level 
and resume treatment***. 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
13 
 
All patients will undergo a MUGA scan prior to enrollment in the study.  Patients proceeding to a 
second cycle of therapy (BCG followed by sunitinib) will undergo a MUGA scan prior to initiation of 
the second cycle.  Patients with an ejection fraction lower than the institutional lower limit of normal 
will not receive further study treatment per protocol and will be offered alternative therapy as 
directed by the treating clinician.   
11.0 PHARMACEUTICAL INFORMATION 
11.1 ™ TICE BCG 
Formulation and Packaging 
TICE BCG Live (intravesical) is a freeze-dried preparation made from the Connaught strain of 
Bacillus Calmette and Guerin, which is an attenuated strain of Mycobacterium bovis supplied as a 
vial containing 50 mg of freeze-dried BCG.   
Preparation and Dispensing 
The preparation of TICE BCG suspension should be done using aseptic technique.  To avoid cross-
contamination, parenteral drugs should not be prepared in areas where BCG has been prepared.  A 
separate area for preparation of the  TICEsuspension is strongly recommended.  All equipment, 
supplies and receptacles in contact with  TICE should be handled and disposed of as biohazardous.  
The individual preparing the TICE should wear gloves, eye protection, and take precautions to avoid 
contact of BCG with broken skin.  If preparation is not performed under a biocontaminant hood, a 
mask and gown may be worn to avoid inhalation or inadvertent exposure to BCG with broken skin.   
TICE should not be handled by persons with an immunologic disorder.   
Do not remove the rubber stopper from the vial.   
(Using Syring Method). 
  Drawn 1 ml of sterile, preservation-free saline (o.9% Sodium Chloride Injection U.S.P.) at 4-25oC, 
into a small syringe (e.g., 3 ml) and add to one vial of TICE BCG to resuspend.  Gently swirl the vial 
until a homogenous suspension is obtained.  Avoid forceful agitation which may cause clumping of 
the mycobacteria.  Dispense the cludy TICE BCG suspension into the top end of a catheter-tip syringe 
which contains 49 ml of saline diluent, bringing the total volume to 50 ml.  To mix, g ently rotate the 
syrine. 
 
(Using Reconstituion Accessories) 
Reconsitituion Accessories may be provided with each TICE BCG product order.  Refer to the 
Instructions For Use provided with the accessories for a full description of the product 
reconstitution procedures using these accessories. 
Administration 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
14 
 
A urethral catheter is inserted into the urinary bladder under aseptic conditions, the bladder is 
drained and then  TICE BCG is instilled slowly by gravity, following which the catheter is withdrawn. 
 The patient should lie prone for the 1st 15 minutes and can be up thereafter.  At the end of 2 hours, 
the patient should void seated and should increase fluid intake to flush the bladder.   
Side effects: 
The following side effects, as well as their frequency, have been observed in BCG clinical studies:  
• 
Likely (50% or more): dysuria. 
• 
Frequent (10-50%): urinary frequency, malaise, hematuria, fever (>38 C), chills, cystitis, 
urinary urgency, nausea/vomiting, anemia,  urinary tract infection 
• 
Occasional (1-10%): bladder cramps/pain, anorexia, renal toxicity, genital pain, 
arthralgia/myalgia, urinary incontinence, diarrhea, contracted bladder, leukopenia 
• 
Rare (less than 1%): coagulopathy, abdominal pain, liver involvement, systemic infection, 
pulmonary infection, cardiac (unclassified), headache, skin rash, tissue in urine, constipation, 
fatigue, local infection, dizziness, thrombocytopenia, ureteral obstruction, and flank pain.   
Procedure for Handling Drug Spills 
After use, unused product, packaging and all equipment and materials used for instillation of the 
product (eg, syringes, catheters) should be placed immediately in a container for biohazardous 
materials and disposed according to local requirements applicable to biohazardous materials.  Spills 
and/or voided urine during the 6 hours following  TICE BCG administration should be disinfected 
with an equal volume of 5% hypochlorite solution (undiluted household bleach) and allowed to 
stand for 15 minutes before cleaning or flushing toilet.   
OVERDOSAGE 
Overdosage occurs if more than one vial of  TICE  BCG is administered per instillation.  If overdosage 
occurs, the patient should be closely monitored for signs of active local or systemic infection.  For 
acute local or systemic reactions suggesting active infection, an infectious disease specialist 
experienced in BCG complications should be consulted. 
Drug Storage  
The reconstituted TICE BCG should be kept refrigerated (2-8o C), protected from exposure to direct 
sunlight, and used within 2 hours.  Unused solution s hould be discarded after 2 hours. 
Compliance 
Patients will be administered the treatment by a healthcare provider. 
11.1.1 AGENT ORDERING  
 Commercial supplies of BCG will be used.     
11.2 PHARMACEUTICAL INFORMATION: SUNITINIB 
Formulation and Packaging 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
15 
 
SUNITINIB is a small molecule inhibitor of the receptor tyrosine kinases VEGFR, PDGFR, KIT, and 
FLT3.  SUNITINIB will be supplied as hard gelatin capsules containing 12.5-mg, 25-mg or 50-mg 
equivalents of SUNITINIB free base.   
Preparation and Dispensing 
SUNITINIB will be dispensed as capsules at the beginning of each treatment cycle. In case of dose 
modification, patients will be requested to return all of their previously dispensed medication to the 
clinic.  Capsules will be counted and patients will be dispensed the appropriate number of capsules 
based on the new dose level.  
Administration 
Administration will be performed on an outpatient basis. The dose should be taken once daily 
without regard to meals. Grapefruit and/or grapefruit juice should be avoided during sunitinib 
administration.  The study investigator may implement dose suspension and/or reduction in order 
to ensure patient safety.  
Side effects: 
The following side effects, as well as their frequency, have been observed in SUNITINIB clinical 
studies:  
• 
Likely (50% or more): fatigue. 
• 
Frequent (10-50%): diarrhea, nausea, upset stomach, taste disturbances, 
stomatitis/mucositis, vomiting, constipation, yellowing of the skin, anorexia, 
arthralgia and myalgia, hypertension, dermatitis, headache, blisters and/or 
rash in hands and feet which may be painful, increased lipase and amylase, 
hair color changes, shortness of breath, edema, dehydration.  
• 
Occasional (1-10%): nosebleeds, leucopenia/neutropenia, anemia, 
thrombocytopenia, insomnia, cough, fever, increased/more frequent eye 
tearing, alopecia, increase creatinine, increased LFTs, reduced ejection 
fraction, increased cardiac enzymes. 
• 
Rare (less than 1%): bleeding requiring transfusion (including bleeding into 
the tumor), thrombosis, infection, hypoadrenalism, increased TSH, 
hypothyroidism, decreased blood flow to the brain, pancreatitis, myocardial 
infarction, bowel perforation/intestinal fistulae, pneumothorax, seizure, 
temporary loss of vision. One patient developed thrombosis of the portal vein. 
Procedure for Handling Drug Spills 
Following direct contact with skin, the contents of the capsules may cause yellow discoloration of 
the exposed area.  The exposed area should be washed with soap and water immediately. 
OVERDOSAGE 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
16 
 
No overdose of SUNITINIB was reported in completed clinical studies. In non-clinical studies 
mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m2) in rats. At this 
dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular 
discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were 
observed at lower doses when administered for longer durations. Treatment of overdose with 
SUNITINIB should consist of general supportive measures. There is no specific antidote for 
overdosage with SUNITINIB. If indicated, elimination of unabsorbed drug should be achieved by 
emesis or gastric lavage. 
Drug Storage  
Since SUNITINIB may be light sensitive, the capsules will be stored in the bottles in which they are 
received to protect the compound from light.  Bottles containing SUNITINIB capsules must be stored 
at controlled room temperature (15-30°C). 
Compliance 
Patients will be required to return all bottles of study medication at the beginning of each cycle.  The 
number of capsules remaining will be documented and recorded.  
11.2.1 AGENT ORDERING  
Sunitinib may be requested by the principal investigator (or their authorized designees).  See 
Appendix E for drug request forms.   
11.2.2 AGENT ACCOUNTABILITY 
The investigator, or an approved representative, e.g. pharmacist, will ensure that all investigational 
products are stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements.  All study drug supplies must be kept in a locked limited 
access room.  The study drug must not be used outside the context of the protocol.  Under no 
circumstances should the investigator or other site personnel supply study drug to other 
investigators, patients, or clinics, or allow supplies to be used other than directed by this protocol.  
The investigator must maintain adequate records documenting the receipt, use, loss or other 
deposition of the investigational product, including batch or code numbers, and account for its 
disposition on patient-by-patient basis, including specific dates and quantities.  The prescribed dose 
should also be recorded in the patient’s medical records. 
Destruction must be adequately documented. 
12.0 CORRELATIVE STUDIES: 
Evaluation of biomarkers in tissue, urine, and serum 
Serum levels of biomarkers of the vascular endothelial growth factor receptor (VEGF-R) pathway 
including VEGF and  soluble VEGFR-2 (sVEGFR-2) have been serially measured in a Phase I [29] as 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
17 
 
well as a phase II [30] study of SUNITINIB in patients with renal cell cancer.   In these studies, VEGF 
was found to be increased and sVEGF-R2 levels decreased by the end of each dosing cycle (day 28).  
After two weeks off therapy, levels returned to near baseline (day 1).  Differences in day 1 and day 
28 levels were statistically significant.  In addition, in patients with metastatic renal cell carcinoma, 
when mean marker level changes were correlated with tumor response, larger proportional changes 
in VEGF and sVEGFR-2 levels were observed in patients exhibiting objective responses compared 
with those exhibiting stable or progressive disease [31].   
As described above, VEGF inhibition is likely important in BCG’s effect on bladder cancer.  VEGF 
receptors are present in the normal urothelium and are also upregulated during inflammation such 
as that occurring in interstitial cystitis.  BCG is known to cause bladder inflammation and therefore 
may cause upregulation of VEGFR receptors in normal as well as malignant bladder cells.[27]  Thus 
the combination of BCG followed by sunitinib may sensitize bladder tumors to response to BCG by 
blocking the VEGF receptor pathway.  Alternatively, tumor cells not affected by BCG may be targeted 
by sunitinib thus providing an opportunity to consolidate complete response to therapy.   
Additionally, other tissue markers may provide important information for patient stratification.  For 
example, p53 mutation, which is common even in non-muscle invasive bladder cancer [32],  may 
also be involved in regulated angiogenesis and response to hypoxia [33]  Thus, the p53 status of 
patients may alter responses to sunitinib.    Another important tissue marker is HIF1a, a marker 
upregulated with tissue hypoxia.  Elevated tissue levels of HIF1a may indicate activation of the VEGF 
pathway, and thus indicate patients who would be more likely to respond to treatment [35]  Each of 
these additional hypotheses can be tested using formalin-fixed, paraffin-embedded tissues subjected 
to immunoperoxidase staining after antigen retrieval [ 34].   
Urine represents an ideal medium to evaluate response to therapy in patients with localized bladder 
cancer as it may directly indicate the response to therapy.  Further, based on preliminary results 
described previously, serum levels of biomakers may also be informative.  We will investigate the 
effect of BCG and sunitinib therapy on urinary and serum levels of various VEGFs, soluble VEGF 
receptors, and cytokines IL8, IL6, interferon gamma, and interferon alpha.  Measurements will be 
performed using commercially-available ELISA kits.   Utility of additional biomarkers (e.g., PDGF, 
[35]) will be evaluated on a pilot basis.   
Correlation of changes in VEGF, VEGFR, p53, and other cytokine expression to response will be 
explored.  Markers will be grouped based on terciles of the distribution.  Bivariate relationships 
between the expression level and response status will be assessed with the Mantel-Haenszel chi-
square test.  Logistic regression will be used to assess the effect of combining markers to predict 
response.  Differences in time to recurrence by expression level will be illustrated by Kaplan-Meier 
plots and tested using the log-rank test.  Due to the sample size and the number of factors we will be 
statistically testing, these analyses will be considered exploratory until confirmed in a larger, 
independent, clinical trial.  
Procedures and Methods: 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
18 
 
• 
Voided urine and serum will be obtained as outlined on the study calendar.  If BCG is 
given locally no specimens need to be obtained at Week 1 and Week 6 visits.   In 
addition, a bladder biopsy will be obtained at the 3 month endoscopic biopsy to 
assess response.  These specimens will only be obtained for the first study cycle. 
• 
Urine will be kept on ice until it can be centrifuged in  the  research laboratory.  The 
urine and pellet will aliquoted into separate tubes, codes, and stores at -80⁰C in the 
research laboratory. 
• 
Tissue will collected at the time of bladder biopsy at 3 months and processed with 
formalin fixation and paraffin-embedding in the Pathology Department, following the 
standard operating procedure of the previously approved University of Michigan 
Bladder Cancer (Tissue/Blood/Urine/Data) Bank (IRB 1996-0379).  Blocks and 
tissue sections will be stored in research lab until processed. 
• 
Tissue biomarker standardization will be performed by microscopic evaluation in 
collaboration with a pathologist.  Each assay will be performed with positive and 
negative control tissues from comparisons.  Responses will be scored based on the 
number of cells staining positive and the level of positivity (0-3+). 
• 
Urine biomarker standardization will be based on urine creatinine measurements. 
 
 
13.0 STUDY CALENDAR:  


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
19 
 
* voided urine cytology obtained in clinic, instrument urine cytology obtained in operating room 
† Medical Oncologist will prescribe sunitinib and monitor for toxicity during treatment 
1 If BCG is given locally no specimens need to be obtained at the Week 1 and Week 6 visits. 
Calendar 2:  Maintenance BCG/Surveillance Schedule (+/- 3 weeks around each time point allowed) 
 
Month 3* 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
 
Cysto 
BCG# 
Cysto 
BCG# 
 
Cysto 
BCG# 
Cysto 
BCG# 
Cysto 
BCG# 
Required studies 
 
 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
History and physical 
x 
 
x 
 
 
x 
 
x 
 
x 
 
Toxicity assessment 
 
x 
 
x 
 
 
x 
 
x 
 
x 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
Dipstick urine 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Urine cytology 
x 
 
x 
 
 
x 
 
x 
 
x 
 
TESTS 
 
 
 
 
 
 
 
 
 
 
 
Cystoscopy 
x 
 
x 
 
x 
x 
 
x 
 
x 
 
* after CR to BCG at 1st or 2nd induction course, # BCG is a 3 week course
 
 
Week 1-6 
BCG Course 1 
Week 8-12† 
Sunitinib cycle 1 
TURBT or 
bladder 
biopsy 
Therapeutic Plan 
Required studies 
Pre-study 
Week1 
Week 6 
Week  
8 
Week  
10 
Week  
12 
Week 14 
1.  Residual/Recurrent disease 
without progression: 
a.  Negative MUGA scan-if positive, 
proceed to 3.   
b.  2nd cycle of BCG followed by 
sunitinib (as per week 1-14) 
c.  alternative treatment plan per 
treating clinician 
2.  No residual disease (Calendar 
2): patient will proceed to 
maintenance BCG therapy per 
institutional standard  
a.  alternative therapy may be 
chosen on maintenance at 
patient/physician discretion 
3.  Disease progression or 
patient/clinician desire: proceed 
to alternative treatment per 
standard of care 
PHYSICAL 
 
 
 
 
 
 
 
History and Physical 
x 
 
 
X 
X 
x 
 
ECOG performance status 
x 
 
 
X 
X 
x 
 
Medication check 
x 
 
 
X 
x 
x 
 
Toxicity assessment 
 
 
 
X 
X 
X 
 
LABORATORY/ STUDIES 
 
 
 
 
 
 
 
CBCPD 
x 
 
 
X 
X 
X 
 
Comprehensive panel 
x 
 
 
X 
 
x 
 
Magnesium 
 
 
 
X 
 
x 
 
EKG 
x 
 
 
 
 
 
 
Dipstick Urine 
 
x 
x 
 
 
 
 
Urine cytology* 
x 
 
 
 
 
 
x 
PT/PTT 
x 
 
 
 
 
x 
 
TSH 
x 
 
 
 
 
 
 
MUGA Scan 
x 
 
 
 
 
 
 
SPECIMEN SAMPLES 
 
 
 
 
 
 
 
Urine* 
 
X1
X1 
X 
 
x 
x 
Bladder biopsy 
 
 
 
 
 
 
x 
Serum 
 
X1 
X1 
x 
 
x 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
Chest radiograph 
x 
 
 
 
 
 
 
CT  or  MRI abdomen/ pelvis 
or IVP 
x 
 
 
 
 
 
 
Cystoscopy or report 
confirming eligibility 
x 
 
 
 
 
 
 
Drug: Sunitnib 
 
 
 
X 
 
 
 
 
Dispense BP log, Study drug 
info, and medication diary 
 
 
 
X 
 
 
 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
20 
 
14.0 MEASUREMENT OF EFFECT 
For the purposes of this study, patients will be assessed for response at 3 months and 6 months.  
Continued response assessment during maintenance BCG will be as outlined by the study calendar 
above.  Further imaging evaluation is as clinically indicated.  Patients will be followed for a total of 2 
years or 2 years following complete response.   
14.1 DEFINITIONS 
• 
Recurrence/Residual disease 
Recurrcent/residual urothelial carcinoma of the lower urinary tract is defined as any 
evidence of tumor by biopsy and/or urine cytology within the urinary bladder or prostatic 
urethra proximal to the striated urethral sphincter.  Upper tract urothelial carcinoma 
(ureters, renal pelvis) does not constitute recurrent disease.  Exam under anesthesia at the 
time of biopsy should be normal. If not consider 3-dimensional axial imaging to evaluate for 
progression. 
• 
Progression (to muscle invasive disease) 
This is defined as any tumor stage > T1 found on scheduled repeat biopsy at 3 or 6 months 
and any biopsy performed thereafter.  Locally advanced disease identified on 3-dimensional 
axial imaging as tumor extension into the perivesical fat will also constitute disease 
progression.   
• 
Metastases 
 
Evidence of disease outside the bladder (lymphadenopathy or metastatic site). 
• 
Urine Cytology 
• 
Negative Urine cytology constitutes a negative test result 
• 
Positive Urine cytology constitutes evidence of disease 
• 
Any finding other than negative or positive will be considered negative 
 
An inadequate specimen will be repeated 
• 
Cystoscopic biopsy 
• 
In the absence of visible disease, random biopsies will be obtained at the discretion 
of the treating physician.  Documentation of any urothelial carcinoma will constitute 
residual disease.  Reactive changes, dysplasia, or other equivocal findings will be 
reviewed by the study team with the pathologist and treating physician to make a 
determination of residual disease.  A completely negative biopsy will be considered 
no evidence of residual disease when combined with the results of the urine cytology 
study. 
• 
Cystoscopic biopsy should include an exam under anesthesia-  if the clinician reports 
a concerning finding on exam, this should be confirmed by imaging to document 
recurrent or progressive disease.   
• 
Exam under anesthesia 
• 
Normal:  bladder mobile, no palpable bladder mass 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
21 
 
• 
Abnormal may constitute any of the following 
o Fixed bladder 
o Palpable bladder mass 
• 
Findings on the prostate exam are not considered for normal or abnormal for 
the purpose of the study unless the clinician determines that abnormal 
prostate exam constitutes local extension of bladder cancer 
• 
Imaging 
• 
Follow-up imaging as clinically indicated.     
 
14.2 GUIDELINES FOR DOCUMENTING RESIDUAL DISEASE, RECURRENCE, PROGRESSION, OR 
METASTASES 
 
Residual/Recurrent disease 
• 
Will be assessed at 3 and 6 months, as clinically indicated (Exam under 
anesthesia should be normal- if not see progression) 
Urine cytology* 
Cystoscopic 
Biopsy* 
Determination 
Negative/other 
Negative 
No residual disease 
Negative/other 
Positive 
Residual disease 
Positive 
Positive 
Residual Disease 
Positive 
Negative 
Residual disease 
 
 
 
Abnormal exam under anesthesia of the bladder requires follow-up imaging 
Disease progression or metastases: assessed at 3 and 6 months and as clinically indicated 
Cystoscopic biopsy 
Exam under 
anesthesia 
Other Tests 
Determination 
Negative 
Negative 
N/A 
No progression 
Negative 
Positive 
Confirmation by repeat 
imaging, biopsy or other 
tests as above 
If confirmation negative, then no 
progression, If +, then progression or 
metastases depending on location- see 
defns 
Positive ≤ stage T1 
Negative 
N/A 
Residual/recurrent disease, no 
progression 
Positive ≤ stage T1 
Positive 
Confirmation by repeat 
imaging, biopsy or other 
tests as above 
If confirmation negative, then 
residual/recurrent disease, If +, then 
progression or metastases depending 
on location-see defns 
Positive > T1 
Negative 
Further imaging may be 
warranted at the 
discretion of the treating 
clinician 
Progression 
Positive > T1 
Positive 
Confirmation by repeat 
imaging, biopsy or other 
tests as above 
Progression or metastases as defined by 
definition above 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
22 
 
14.3 RESPONSE CRITERIA 
Complete Response (CR): 
Negative/other urine cytology + negative cystoscopic biopsy, 
negative exam under anesthesia (if positive, imaging must be 
negative) 
Residual Disease: 
 
A positive cytology and/or a positive cystoscopic biopsy, 
negative exam under anesthesia (if positive, imaging must be 
negative) 
Progressive Disease (PD): 
A biopsy demonstrating > stage T1 bladder tumor.  A positive 
exam under anesthesia confirmed by imaging constitutes 
progression.   
Metastases: 
 
 
A confirmed site of disease by definitions above of urothelial 
malignancy outside the bladder.   
14.4 DURATION OF RESPONSE 
• 
Complete response assessed in every subject receiving at least one dose of sunitinib at 3 
months.  This will be determined as a percentage of the patients.   
• 
Complete response will be assessed in all those patients undergoing a second cycle of BCG 
followed by SUNITINIB. 
o Those responding to an initial course and going to maintenance therapy will not be 
evaluated for CR at 6 months 
o Those patients unable to receive a second induction course of BCG followed by 
sunitinib will not be evaluated for CR at 6 months 
• 
Recurrence free survival:  
o Recurrence definition as above 
o Assessed from time of study enrollment until recurrence or 2 years 
o Patients receiving a second induction course are assumed to have residual disease, 
not recurrence 
 
Recurrence free survival is therefore assessed from study enrollment until 
recurrence or two years 
o Assessed in those patients with intact bladder only 
o Assessed only in those completing one induction course of BCG and receiving any 
sunitinib 
• 
Progression free survival:  
o Progression definition as above 
o Assessed from time of study enrollment until progression or 2 years 
o Patients receiving a second induction course are assumed to have residual disease 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
23 
 
 
Progression free survival is therefore assessed from study enrollment until 
progression or two years 
o Assessed in those patients with intact bladder only 
o Assessed only in those completing one induction course of BCG and receiving any 
sunitinib 
• 
Metastases free survival 
o Definition above 
o Assessed in those patients completing one induction course of BCG and any sunitinib 
o Assessed from time of study enrollment to disease or two years 
15.0 REGULATORY AND REPORTING REQUIREMENTS 
• 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 3.0 will be utilized for adverse event reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 3.0.  A list of 
adverse events that have occurred or might occur can be found in Sections of Pharmaceutical 
Information for SUNITINIB and BCG.   
 
• 
SAE Definition.  A SAE is any adverse event, without regard to causality, that is life-
threatening or that results in any of the following outcomes: death; in-patient hospitalization 
or prolongation of existing hospitalization; persistent or significant disability or incapacity; 
or a congenital anomaly or birth defect.  Any other medical event that, in the medical 
judgment of the Principal Investigator, may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed above is also considered an SAE.  
A planned medical or surgical procedure is not, in itself, an SAE.  Also specifically excluded 
from this definition of SAE is any event judged by the Principal Investigator to represent 
progression of the malignancy under study, unless it results in death within the SAE 
Reporting Period. 
 
• 
SAE Reporting Period. The SAEs that are subject to this reporting provision are those that 
occur from after the first dose of the study drug through 28 days after discontinuation of 
study drug(s).    
15.1 EXPEDITED ADVERSE EVENT REPORTING 
• 
Expedited reports are submitted via an adverse event reporting form to the IRB which will 
be created as part of the clinical report forms used for the study.  The adverse event will also 
be reported to Pfizer via fax as well as a Medwatch form. Those AEs that do not require 
expedited reporting must be reported in routine study data submissions.  AEs reported in 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
24 
 
expedited review must also be reported in routine study data submissions including the 
Data and Safety Monitoring report. 
• 
Expedited Reporting Guidelines –Reporting Requirements for Adverse Events That Occur 
Within 28 Days of the Last Dose of the Investigational Agent.  
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
& Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Un-expected 
Expected 
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-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1  Adverse events with attribution of possible, probable, or definite that occur greater than 28 days after the 
 last dose of treatment  require reporting as follows: 
IRB 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
IRB 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an IRB 24-hour notification is not required for death clearly related to progressive disease, a full report is required as 
outlined in the table.  
 
Note:  All deaths on study must be reported using expedited reporting regardless of causality. 
 Attribution to treatment or other cause should be provided. 
• 
Expedited AE reporting timelines defined: 
 
“24 hours; 5 calendar days” – The investigator must initially report the AE within 24 
hours of learning of the event followed by a complete report within 5 calendar days 
of the initial 24-hour report. 
 
“10 calendar days” - A complete  report on the AE must be submitted within 10 
calendar days of the investigator learning of the event.  
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
25 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of designation 
as expected or unexpected and attribution. 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported.  
• 
Use the protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
• 
Expected adverse events are identified in Sections above. 
• 
For Hospitalization only – Any medical event equivalent to CTCAE grade 3, 4, or 5 
that precipitated hospitalization (or prolongation of existing hospitalization) must 
be reported regardless of designation as expected or unexpected and attribution.  
 
Serious Adverse Event (SAE) Reporting to Pfizer and The University of Michigan 
Within 24 hours of first awareness of the event (immediately if the event is fatal or life-threatening), 
the Principal Investigator at the site of the event will report to the University of Michigan any 
Serious Adverse Event ("SAE," as defined above) that occurs during the SAE reporting period (from 
after the first dose of the study drug through 28 days after discontinuation of study drug).   
Within 24 hours of first awareness of the event (immediately if the event is fatal or life-threatening), 
Principal Investigator will report to the Pfizer by facsimile any Serious Adverse Event ("SAE," as 
defined below) that occurs during the SAE reporting period (as defined below) in a Study subject 
assigned to receive the Pfizer Product.  Principal Investigator will report such SAEs using an FDA 
MEDWATCH form and the Serious Adverse Event Fax Cover Sheet provided by Pfizer.  SAEs should 
be reported as soon as they are determined to meet the definition, even if complete information is 
not yet available.   
 
 SAE Reporting Period.  The SAEs that are subject to this reporting provision are those that occur 
from after the first dose of the Pfizer Product through 28 days after discontinuation of the Pfizer 
Product.   
 
 Follow-Up Information.  Institution will assist Pfizer in investigating any SAE and will provide any 
follow-up information reasonably requested by Pfizer. 
 
 Regulatory Reporting.  Reporting an SAE to Pfizer does not relieve Institution of responsibility for 
reporting it to regulatory authorities, as required. 
15.2 DATA REPORTING 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
26 
 
• 
All data must be entered in “real time” such that all data are current.  A study database 
will be created by the Clinical Trials Office of the Department of Urology for this 
purpose.   
Responsibility of the Principal Investigator  
• 
The Principal investigator will be the single liaison with Pfizer.  The Principal 
Investigator is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must 
not be rewritten or modified by anyone other than the Principal Investigator.  There 
will be only one version of the protocol. 
• 
All reporting requirements to the IRB / Pfizer are the responsibility of the Principal 
investigator.  
• 
The Principal Investigator is responsible for the timely review of Adverse Events 
(AE) to assure safety of the patients. 
• 
The Principal Investigator will be responsible for the review of and timely 
submission of data for study analysis. 
• 
Any manuscripts reporting the results of this clinical trial will be provided to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 14 days from the date of receipt for review.  
Copies of abstracts will be provided to Collaborator(s) for courtesy review as soon as 
possible prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.   
16.0 STATISTICAL CONSIDERATIONS 
 
16.1 STUDY DESIGN/ENDPOINTS 
The primary objective of this trial is to estimate the complete response rate in patients with high-
risk non-muscle invasive bladder cancer treated with intravesical bacillus Calmette Guerin followed 
by daily oral sunitinib for 4 weeks as assessed by urine cytology, cystoscopic biopsy, and exam 
under anesthesia.  If the response rate is 55% or less, there would be little interest in pursuing this 
therapy in further studies.  In this case, we would like to terminate the trial early and consider a new 
therapy.  If the response rate is 75% or more, further study would be proposed based on the 
estimates produced in this trial.  To minimize the number of patients treated, the Minimax two-stage 
accrual design [Controlled Clinical Trials 10:1-10 1989] has been adopted. 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
27 
 
We will accrue 24 high-risk non-muscle invasive bladder cancer patients.  If less than 16 responses 
are seen, the trial will stop. If 16 or more responses are seen, an additional 12 patients will be 
entered.  If 25 or more of the 36 evaluable patients achieve a complete response, then further 
studies will be proposed. 
This trial design provides 80% statistical power at the 5% significance level. If the response rate was 
as low as 55%, there would be a 83% chance of stopping the trial after just 24 patients and only a 
4.9% chance of going on to stage two (false positive error). However if the true response rate was 
75%, there would only be a 12% chance of stopping the study early and a 19.9% chance of rejecting 
the therapy (false negative error).  Evaluable patients will include all patients who receive at least 
one dose of sunitinib.  Patients who are removed from the study before treatment with sunitinib 
with be replaced.   
16.2 ANALYSES 
The primary endpoint for this study will be the complete response rate.  This rate will be reported 
along with 95% confidence intervals.   
This study has several secondary endpoints.  Response rates at 6 months will be reported with 95% 
confidence intervals for patients with an intact bladder.   Kaplan-Meier estimates will be used to 
describe recurrence-free survival, including 2-year recurrence-free survival estimates.  Toxicity of 
this therapy will be described, both overall and by grade.  Toxicity rates will be tabulated by type 
and category. 
Correlation of changes in VEGF, VEGFR, p53, and other cytokine expression to response will be 
explored.  Markers will be grouped based on terciles of the distribution.  Bivariate relationships 
between the expression level and response status will be assessed with the Mantel-Haenszel chi-
square test.  Potential analyses will include logistic regression with an outcome of response and 
Kaplan-Meier methods for time to recurrence.  Differences in time to recurrence by expression level 
will be illustrated by Kaplan-Meier plots and tested using the log-rank test.  Due to the sample size 
and the number of factors we will be statistically testing, these analyses will be considered 
exploratory until confirmed in a larger, independent, clinical trial.  
16.3 PATIENT ACCRUAL 
Based on previous experience, the accrual to this trial is expected to be 3 eligible patients per month. 
 Thus, the accrual period for the first stage is expected to be 8 months.  The second stage is expected 
to take an additional 3 months to accrue the final 12 patients. 
16.4 REPORTING AND EXCLUSIONS 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
28 
 
16.4.1 EVALUATION OF TOXICITY.  All patients will be assessable for toxicity from the time 
of their first treatment with study drug. 
16.4.2 EVALUATION OF RESPONSE.  All eligible patients included in the study must be 
assessed for response to treatment, even if there are major protocol treatment deviations or 
if they are taken off study.  Evaluation of response will be performed as outlined in Section 
14 of the protocol.   
All of the patients who met the eligibility criteria and receive at least one dose of sunitinib should be 
included in the main analysis.  All conclusions should be based on all eligible patients. Sub analyses 
may then be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation 
of treatment, major protocol violations, etc.).  However, these subanalyses may not serve as the basis 
for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from 
the analysis should be clearly reported.  The 95% confidence intervals should also be provided.  
  
17. DATA MANAGEMENT AND MONITORING: 
17.1 DATA COLLECTION/ENTRY:  Clinical report forms will be developed by the 
principal investigator and study coordinator for data collection and entered into a password 
protected database which will be created at the initiation of the trial. 
Adverse events, including all toxic effects of treatment, will be tabulated, individually 
summarized by body system and to severity or toxicity grade. See section 15 for adverse 
event reporting. 
17.2 DATA SECURITY AND CONFIDENTIALITY: 
To ensure security and confidentiality, participant names are not part of the research record. 
 Participant initials, date of birth and a study-specific identification number are the sole 
identifiers.  Physical security and systematic backup for the database will occur.  Access to 
data rigorously complies with HIPAA requirements, governed by HIPAA’s “minimum 
necessary” principle.  Source documentation will be available to support the computerized 
database. 
 
 
17.3 QUALITY ASSURANCE/DATA AND SAFETY MONITORING 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
29 
 
The University of Michigan Comprehensive Cancer Center Data and Safety Monitoring Board 
(UMCCC DSMB) is the DSMB for this study responsible for monitoring the study’s scientific 
progress, and accrual and any serious adverse events.  
17.3.1 DATA SAFETY AND MONITORING: 
There will be scheduled meetings that will be conducted every 3 months or more frequently 
depending on the activity of the study.  These meetings will include the principal 
investigator, study coordinator and if available the Co-Investigators and study statistician.     
During these meetings the investigators will discuss matters related to: 
1. Safety of protocol participants (AE reporting). 
2. Validity and integrity of the data. 
3. Enrollment rate relative to expectation, characteristics of participants 
4. Retention of participants, adherence to protocol (potential or real protocol 
violations). 
5. Data completeness. 
 
These meeting are to be documented by the site coordinator, using the Protocol Specific Data and 
Safety Monitoring Report (DSMR). The reports will be signed by the site principal investigator and 
submitted to the UMCCC DSMB on a quarterly basis with other pertinent documents.  The report 
generated by the DSMB will be submitted to the IRB according to institutional standards. 
The Study Coordinator assigned to the trial will be responsible for completing the Protocol Deviation 
Form.  The reports will be signed by the principal investigator and submitted to the UMCCC DSMB 
on a quarterly basis with the DSMR. 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
30 
 
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1. 
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2. 
Avritscher, E.B., et al., Clinical model of lifetime cost of treating bladder cancer and associated 
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3. 
Lokeshwar, V.B. and M.G. Selzer, Urinary bladder tumor markers. Urol Oncol, 2006. 24(6): p. 
528-37. 
4. 
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5. 
Lee, C.T., et al., Early-stage bladder cancer surveillance does not improve survival if high-risk 
patients are permitted to progress to muscle invasion. Urology, 2007. 69(6): p. 1068-72. 
6. 
Gilbert, S.M., et al., Measuring health-related quality of life outcomes in bladder cancer 
patients using the Bladder Cancer Index (BCI). Cancer, 2007. 109(9): p. 1756-62. 
7. 
Stein, J.P. and D.G. Skinner, Radical cystectomy for invasive bladder cancer: long-term results 
of a standard procedure. World J Urol, 2006. 24(3): p. 296-304. 
8. 
Solsona, E., et al., Effectiveness of a single immediate mitomycin C instillation in patients with 
low risk superficial bladder cancer: short and long-term followup. J Urol, 1999. 161(4): p. 1120-3. 
9. 
Sylvester, R.J., et al., Bacillus calmette-guerin versus chemotherapy for the intravesical 
treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of 
randomized clinical trials. J Urol, 2005. 174(1): p. 86-91; discussion 91-2. 
10. 
Folkman, J., What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst, 
1990. 82(1): p. 4-6. 
11. 
O'Brien, T.S. and A.L. Harris, Angiogenesis in urological malignancy. Br J Urol, 1995. 76(6): p. 
675-82. 
12. 
Dickinson, A.J., et al., Quantification of angiogenesis as an independent predictor of prognosis 
in invasive bladder carcinomas. Br J Urol, 1994. 74(6): p. 762-6. 
13. 
Horak, E.R., et al., Angiogenesis, assessed by platelet/endothelial cell adhesion molecule 
antibodies, as indicator of node metastases and survival in breast cancer. Lancet, 1992. 340(8828): p. 
1120-4. 


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14. 
Goddard, J.C., et al., Microvessel density at presentation predicts subsequent muscle invasion in 
superficial bladder cancer. Clin Cancer Res, 2003. 9(7): p. 2583-6. 
15. 
Canoglu, A., et al., Microvessel density as a prognostic marker in bladder carcinoma: 
correlation with tumor grade, stage and prognosis. Int Urol Nephrol, 2004. 36(3): p. 401-5. 
16. 
Chopin, D.K., et al., Increased immunodetection of acidic fibroblast growth factor in bladder 
cancer, detectable in urine. J Urol, 1993. 150(4): p. 1126-30. 
17. 
Nguyen, M., et al., Elevated levels of the angiogenic peptide basic fibroblast growth factor in 
urine of bladder cancer patients. J Natl Cancer Inst, 1993. 85(3): p. 241-2. 
18. 
Brown, L.F., et al., Increased expression of vascular permeability factor (vascular endothelial 
growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol, 1993. 143(5): p. 
1255-62. 
19. 
Bellmunt, J., M. Hussain, and C.P. Dinney, Novel approaches with targeted therapies in bladder 
cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor family. Crit Rev 
Oncol Hematol, 2003. 46 Suppl: p. S85-104. 
20. 
Neal, D.E., et al., Epidermal-growth-factor receptors in human bladder cancer: comparison of 
invasive and superficial tumours. Lancet, 1985. 1(8425): p. 366-8. 
21. 
Neal, D.E., et al., The epidermal growth factor receptor and the prognosis of bladder cancer. 
Cancer, 1990. 65(7): p. 1619-25. 
22. 
Messing, E.M., Clinical implications of the expression of epidermal growth factor receptors in 
human transitional cell carcinoma. Cancer Res, 1990. 50(8): p. 2530-7. 
23. 
Bue, P., et al., Expression of epidermal growth factor receptor in urinary bladder cancer 
metastases. Int J Cancer, 1998. 76(2): p. 189-93. 
24. 
Ferrara, N., The role of vascular endothelial growth factor in pathological angiogenesis. Breast 
Cancer Res Treat, 1995. 36(2): p. 127-37. 
25. 
Ferrara, N. and T. Davis-Smyth, The biology of vascular endothelial growth factor. Endocr Rev, 
1997. 18(1): p. 4-25. 
26. 
Yang, C.C., K.C. Chu, and W.M. Yeh, The expression of vascular endothelial growth factor in 
transitional cell carcinoma of urinary bladder is correlated with cancer progression. Urol Oncol, 2004. 
22(1): p. 1-6. 
27. 
Izawa, J.I., et al., Differential expression of progression-related genes in the evolution of 
superficial to invasive transitional cell carcinoma of the bladder. Oncol Rep, 2001. 8(1): p. 9-15. 


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28. 
Crew, J.P., et al., Vascular endothelial growth factor is a predictor of relapse and stage 
progression in superficial bladder cancer. Cancer Res, 1997. 57(23): p. 5281-5. 
29. 
Mizutani, Y., Y. Okada, and O. Yoshida, Expression of platelet-derived endothelial cell growth 
factor in bladder carcinoma. Cancer, 1997. 79(6): p. 1190-4. 
30. 
Li, N., et al., Expression of vascular endothelial growth factor isoforms and platelet-derived 
endothelial cell growth factor in bladder cancer. Urol Oncol, 2000. 6(1): p. 10-15. 
31. 
Li, S., et al., Prognostic significance of platelet-derived endothelial cell growth factor/thymidine 
phosphorylase expression in stage pT1 G3 bladder cancer. Int J Urol, 2001. 8(9): p. 478-82. 
32. 
Bevers, R.F., K.H. Kurth, and D.H. Schamhart, Role of urothelial cells in BCG immunotherapy 
for superficial bladder cancer. Br J Cancer, 2004. 91(4): p. 607-12. 
33. 
Lamm, D.L., et al., A randomized trial of intravesical doxorubicin and immunotherapy with 
bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. N Engl J Med, 1991. 325(17): p. 
1205-9. 
34. 
Lamm, D.L., et al., Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 
and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology 
Group Study. J Urol, 2000. 163(4): p. 1124-9. 
35. 
Lerner, S.P., et al., Patterns of recurrence and outcomes following induction bacillus Calmette-
Guerin for high risk Ta, T1 bladder cancer. J Urol, 2007. 177(5): p. 1727-31. 
36. 
Gupta, A., et al., Outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma 
treated with radical cystectomy. Urology, 2008. 71(2): p. 302-7. 
37. 
Joudi, F.N., B.J. Smith, and M.A. O'Donnell, Final results from a national multicenter phase II 
trial of combination bacillus Calmette-Guerin plus interferon alpha-2B for reducing recurrence of 
superficial bladder cancer. Urol Oncol, 2006. 24(4): p. 344-8. 
38. 
Slaton, J.W., W.F. Benedict, and C.P. Dinney, P53 in bladder cancer: mechanism of action, 
prognostic value, and target for therapy. Urology, 2001. 57(5): p. 852-9. 
39. 
Pavlovich, C.P., et al., BCG-induced urinary cytokines inhibit microvascular endothelial cell 
proliferation. J Urol, 2000. 163(6): p. 2014-21. 
40. 
Gallagher, D.J., et al. Final results of a phase II study of sunitinib in patients with relapsed or 
refractory urothelial carcinoma. in American Society of Clinical Oncology. 2008. Chicago: J Clin Oncol. 
41. 
Roskoski, R., Jr., Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis 
inhibitor. Biochem Biophys Res Commun, 2007. 356(2): p. 323-8. 


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33 
 
42. 
Silay, M.S. and C. Miroglu, Sunitinib malate and sorafenib may be beneficial at the treatment of 
advanced bladder cancer due to their anti-angiogenic effects. Med Hypotheses, 2007. 
43. 
Faivre, S., et al., Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral 
multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol, 2006. 24(1): p. 25-35. 
44. 
Motzer, R.J., et al., Activity of SU11248, a multitargeted inhibitor of vascular endothelial 
growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal 
cell carcinoma. J Clin Oncol, 2006. 24(1): p. 16-24. 
45. 
DePrimo S, B.C., Smeraglia J, et al, The multitargeted kinase inhibitor sunitinib malate 
(SU11248): soluble protein biomarkers of pharmacodynamic activity in patients with metastatic renal 
cell carcinoma.  . European Journal of Cancer Supplements, 2005. 3(2): p. 420. 
46. 
Saban, M.R., et al., VEGF receptors and neuropilins are expressed in the urothelial and neuronal 
cells in normal mouse urinary bladder and are up-regulated in inflammation. Am J Physiol Renal 
Physiol, 2008. 
 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
34 
 
APPENDICIES  
APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
35 
 
APPENDIX B: NURSING PROTOCOL FOR ADMINISTRATION OF INTRAVESICAL 
BCG ( BACILLUS CALMETTE-GUERIN) 
1. Obtain urinalysis (midstream urine collection) and vital signs (including temperature) 
before each instillation. 
-  urinalysis should be negative for signs of urinary tract infection (wbc, nitrate,            
bacteria) before instillation 
-  gross hematuria is a contraindication to therapy 
2. Medication should be ordered from pharmacy once established that patient can proceed 
with instillation (confirm signed MD order on file prior to patient appointment) 
3. Use precautions during instillation – chemo gown, gloves and wear a TB mask.  (refer to 
infection control guidelines) 
4. Ensure right patient, route, dose and date prior to instillation 
5. Explain procedure to patient before beginning instillation 
6. Insert 12 French Coude catheter for men and French straight catheter for females.  Drain 
bladder and document residual. 
7. Instill solution of 50cc BCG/Normal Saline into the bladder 
8. Remove foley catheter and prevent solution from touching patient’s skin as this can 
cause local irritation. 
9. Patient should be instructed to hold medication/urine for 2 hours. 
10. Dispose of all contaminated materials in a hazardous waste bucket. 
11. Wipe down all surfaces with the Sani-Wipe cloths. 
12. Patient should be advised to sit down when he/she urinates (to avoid splashing of urine) 
for 6 hours post treatment.  He /she should place 2 cups of household bleach in the toilet 
water and allow the bleach to remain for 20 minutes prior to flushing toilet, for 6 hours 
post treatment.   Patient should be advised to cleanse skin with soap and water if 
incontinent of urine/urine spashes on skin surfaces.    
13. Patient should be advised symptoms such as low-grade fever, chills, a flu-like malaise, 
and joint aches are signs that the body is responding to the BCG.  Patients should 
contact the clinic staff/MD is fever noted above 101.5, rash or cough noted or other 
abnormal urinary concerns noted.  
14. Instillations should be spaced 7 days apart. 
15. Document all pertinent information after each instillation including: 
  a.  Date 
  b.  Time 
  c.  Route and catheter size 
  d.  Dosage 
  e.  Assessment of patient 
  f.  Signature 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
36 
 
APPENDIX C: MEDICATION DIARY 
PATIENT INITIAL /MRN: _______ 
 
 
 
CYCLE #:__________ 
Please be sure to fill this out every day and bring this with your study drug bottles (empty or not) to your clinical 
appointment. Please be sure to give this form and the study drug bottles to research nurse or research assistant 
in the clinic. 
 
Date 
# tablets taken 
Time Taken 
Day 1 
 
 
 
Day 2 
 
 
 
Day 3 
 
 
 
Day 4 
 
 
 
Day 5 
 
 
 
Day 6 
 
 
 
Day 7 
 
 
 
Day 8 
 
 
 
Day 9 
 
 
 
Day 10 
 
 
 
Day 11 
 
 
 
Day 12 
 
 
 
Day 13 
 
 
 
Day 14 
 
 
 
Day 15 
 
 
 
Day 16 
 
 
 
Day 17 
 
 
 
Day 18 
 
 
 
Day 19 
 
 
 
Day 20 
 
 
 
Day 21 
 
 
 
Day 22 
 
 
 
Day 23 
 
 
 
Day 24 
 
 
 
Day 25 
 
 
 
Day 26 
 
 
 
Day 27 
 
 
 
Day 28 
 
 
 
 
Have you consumed grapefruit juice while taking study drug? __________ 
 
Patient Signature: _______________________________ Date:  __________ 
 
The following pill count should be filled out by the Hospital Staff: 
# of study drug capsules remaining in the bottle: _____________________ 
 
Name/Signature of the person doing the pill count: _______________________ 
 
Date of the clinic visit: ___________________ 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
37 
 
  
 
APPENDIX D: SITE DRUG REQUEST FORM 
 
Institution 
Name: 
 
 
 
Requestor 
Name:
 
 
 
 
 
 
 
 
(Phone) 
 
(Fax) 
TO: 
Clinical/Scientific Operations – US Oncology 
ATTN: 
Taina Lopez,  Clinical Study Manager 
FAX: 
212.309.0571 
RE: 
Sunitinib Malate (SU011248 L-Malate Salt) Drug Request 
 
Protocol 
Title: 
Phase II study of intravesical bacillus Calmette-Guerin 
followed by oral sunitinib for the treatment of high risk non-
invasive transitional cell carcinoma of the urinary bladder 
 
Principal Investigator: 
Alon Z. Weizer , M.D. 
 
 
Pfizer Protocol Number: 
GA6181UO 
 
Institution Protocol 
Number: 
 
 
FDA IND Number: 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
38 
 
 
* Please note that a 37.5mg dose should be supplied to the patient as 1 x 25mg cap AND 1 x 12.5mg 
cap 
** Please allow a minimum of 10-15 business days for initial shipment and 7-10 business days for 
subsequent shipments.  If you have further questions, please call Taina Lopez at (212) 733-9223.   
 
 
 
Shipping 
Address: 
 
 
 
 
Initial 
Shipment? 
 
Yes 
 
No 
IRB Approval Date: 
 
 
Drug and Strength 
Number of Bottles 
 
 
Sunitinib Malate Capsules 
(30 capsules/bottle) 
 50mg  
 
 
 
 25mg* 
 
 
 
 12.5mg* 
 
 
** 
Date Ordered: 
 
 
 
Date Required: 
 
 
 
 
 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
39 
 
Confidentiality Notice:  The documents accompanying this telecopy transmission contain information belonging to Pfizer, which is 
intended only for the use of the addressee. If you are not the intended recipient, you are hereby notified that any disclosure, copying, 
distribution or the taking of any action in reliance on the contents of this telecopied information is strictly prohibited. If you have received 
this telecopy in error, please immediately notify us by telephone to arrange for the return of the original documents to us.  Thank you. 
 
 APPENDIX E: SERIOUS ADVERSE EVENT FAX COVER SHEET  
Use this fax cover sheet to fax Serious Adverse Events for Investigator-Initiated Research studies. 
 
Fax the completed MedWatch Form FDA 3500A-Mandatory Reporting which can be obtained from the FDA website: 
www.fda.gov/medwatch/getforms.  
 
The MedWatch Form should include the following information in block 5 of the Adverse Events section: 
The complete clinical course of the patient receiving Pfizer drug 
The causality assessment for each Serious Adverse Event 
The action taken for each study drug and for each Serious Adverse Event 
The outcome for each Serious Adverse Event 
 
This cover sheet MUST be attached with each completed MedWatch form. Do not substitute forms/reports or submit 
additional documentation other than what is required.  
 
Do not fax these forms to any additional fax numbers other than the one listed below. 
TO:       Pfizer U.S. Clinical Safety 
FAX:      1-866-997-8322 
FROM: 
DATE: 
TELEPHONE: 
FAX: 
NUMBER OF PAGES  
(INCLUDING COVER SHEET): 
PRODUCT 
Sutent 
PFIZER REFERENCE 
NUMBER 
GA6181UO 
STUDY TITLE 
Phase II study of intravesical bacillus Calmette-Guerin followed by oral sunitinib for the 
treatment of high risk non-invasive transitional cell carcinoma of the urinary bladder 
PATIENT NUMBER 
 
INVESTIGATOR 
Alon Z. Weizer , MD 


AZ Weizer, Phase II Study of BCG followed by Sunitinib for High risk NMIBC 
 
40 
 
APPENDIX F: SELECTED POTENTIAL CYP3A4 DRUG INTERACTIONS 
 
When drugs classified as ‘substrates’ are co-administered with Sunitinib, there is the potential for higher concentrations of the ‘substrate’. 
When  Sunitinib  is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of Sunitinib is the potential 
outcome. The coadministration of ‘inducers’ would potentially lower plasma   Sunitinib concentrations. 
SUBSTRATES 
INHIBITORS 
INDUCERS 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Anti-neoplastics: e.g. 
    Docetaxel 
    Gefitinib 
    Irinotecan 
Taxotere 
Iressa 
Camptosar 
Anti-arrhythmics: e.g. 
    Amiodarone 
    Diltiazem 
    Quinidine 
Cordarone, Pacerone 
Cardizem, Dilacor 
XR 
Cardioquin 
Aminoglutethimide 
Cytadren 
Anti-virals: e.g. 
    Amprenivir 
    Rifampin 
Agenerase 
Rifadin 
 
 
Anti-virals: e.g. 
    Amprenavir 
    Indinavir 
    Nelfinavir 
    Ritonavir 
Agenerase 
Crixivan 
Viracept 
Norvir 
Antibiotics: e.g. 
    Rifabutin 
    Rifampin 
Rifadin 
Mycobutin 
 
 
Anxiolytics: e.g. 
    Diazepam 
    Sertraline 
Valium 
Zoloft 
Cimetadine 
Tagamet 
Anticonvulsants: e.g.   
    Carbamazapine 
    Phenytoin 
    Pentobarbital 
    Phenobarbital 
Tegretol 
Dilantin 
Nembutal 
Luminal 
Cyclosporine 
Sandimmune 
Cyclosporine 
Sandimmune 
Hypericum perforatum (2) 
St. John’s Wort 
Anti-infectives: e.g. 
    Erythromycin 
    Tetracycline 
Erythrocin 
Sumycin 
Antibiotics: e.g. 
    Ciprofloxacin 
    Clarithromycin 
    Doxycycline 
    Enoxacin 
    Isoniazid 
    Telithromycin 
Cipro, Ciloxan 
Biaxin 
Adoxa, Periostat 
Penetrex 
Nydrazid, INH 
Ketek 
 
 
Steroids: e.g. 
    Estrogens, conjugated 
    Estradiol 
    Progesterone 
Premarin 
Climara 
Crinone 
Imatinib 
Gleevec 
  
 
Haloperidol 
Haldol 
Haloperidol 
Haldol 
 
 
Cardiovascular agents:e.g. 
    Digitoxin 
    Quinidine 
Crystodigin 
Cardioquin 
Diclofenac 
Cataflam, Voltaren 
 
 
Anti-hypertensives: e.g. 
    Nicardipine 
    Verapamil 
Cardene 
Calan, Chronovera 
Vasodilators: e.g. 
    Nicardipine 
    Verapamil 
Cardene 
Calan, Chronovera 
 
 
Anesthetics: e.g. 
    Ketamine 
    Lidocaine 
Xylocaine 
Diprivan 
Anesthetics: e.g. 
    Lidocaine 
    Propofol 
Xylocaine 
Diprivan 
 
 
Nefazodone 
     
Serzone 
Anti-depressants: e.g. 
    Nefazodone 
    Sertraline 
Serzone 
Zoloft 
 
 
Cocaine 
 
Anti-fungals: e.g. 
    Itraconazole 
    Ketoconazole 
   Miconazole 
Sporanox 
Nizoral 
Lotrimin, Monistat 
 
 
Ketoconazole 
Nizoral 
Caffeine 
 
 
 
Sildenafil 
Viagra 
Grapefruit juice (1) 
 
 
 
Albuterol 
Ventolin 
 
 
 
 
Carbamazapine 
Tegretol 
 
 
 
 
Lovastatin 
Mevacor