Conditions: Bladder Cancer
Keywords: Dovitinib FGFR3 Mutations BCG-Refractory Urothelial Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
This trial will assess the 6-month complete response rate and toxicity profile of oral dovitinib therapy in BCG-refractory urothelial carcinoma patients with tumors with FGFR3 mutations or over-expression who are ineligible for or refusing cystectomy.

Detailed description:
OUTLINE: This is a multi-center study.

* Dovitinib will be administered 500mg orally in a 5 days on, 2 days off dosing schedule. Day 12 assessments are intended to be performed on the last dosing day of the 2nd week in cycle 1 and cycle 2 and day 26 assessments are intended to be performed on the last dosing day of the 4th week in cycle 1 and cycle 2.
* Standard of Care: Cystoscopy with tumor biopsy, bladder biopsy, urine cytology
* Physician discretion: Anti-emetic medications and/or colony stimulating growth factors

ECOG performance status 0 - 2

Hematopoietic:

* White blood cell count (WBC) \> 3.0 K/mm3
* Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
* Platelets ≥ 100 K/mm3
* Hemoglobin (Hgb) ≥ 9 g/dL

Hepatic:

* Serum total bilirubin: ≤ 1.5 x Upper limit of normal (ULN)
* Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 3.0 x ULN

Renal:

* Serum creatinine ≤ 1.5 x ULN or serum creatinine \> 1.5 - 3 x ULN if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockcroft-Gault equation

Cardiovascular:

No impaired cardiac function or clinically significant cardiac diseases, including any of the following:

* History or presence of serious uncontrolled ventricular arrhythmias
* Clinically significant resting bradycardia
* LVEF assessed by 2-D echocardiogram (ECHO) \< 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan (MUGA), \< 45% or lower limit of normal (whichever is higher)
* Myocardial Infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)within 6 months prior to starting study drug

Arms:
arm 1: Dovitinib will be administered 500mg orally in a 5 days on, 2 days off dosing schedule.

Interventions: intervention 1: Dovitinib
Intervention descriptions: intervention 1: Dovitinib will be administered 500mg orally in a 5 days on, 2 days off dosing schedule. Day 12 assessments are intended to be performed on the last dosing day of the 2nd week in cycle 1 and cycle 2 and day 26 assessments are intended to be performed on the last dosing day of the 4th week in cycle 1 and cycle 2.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Confidential 
Hoosier Cancer Research Network GU12-157 
1 |
 Page 
Protocol Title 
Phase 
II Trial of Dovitinib in BCG-Refractory Urothelial Carcinoma Patients with Tumor 
FGFR3 Mutations or Over-expression: Hoosier Cancer Research Network GU12-157 
 
Sponsor Investigator and Oncology Chair 
Noah M. Hahn, MD 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
The Bunting-Blaustein Cancer Research Building 
1650 Orleans Street 
Baltimore, MD 21287 
Phone: (443) 287-0553 
Fax: (410) 614-7287 
Email: nhahn4@jhmi.edu 
 
Urology Chair 
Timothy A. Masterson, MD 
Indiana University Melvin and Bren Simon Cancer Center 
535 Barnhill Drive, RT 420 
Indianapolis, IN 46202 
Phone: (317) 278-7560 
Fax: (317) 274-0174 
Email: tamaster@iupui.edu 
 
Statistician 
Ziyue Liu, PhD 
Indiana University Department of Biostatistics 
Phone: (317) 278-6734 
Email: ziliu@iupui.edu 
 
Trial Support and Investigational Drug Provided By  
Novartis Pharmaceuticals  
No. CTKI258AUS17T 
 
Investigational New Drug (IND) Application #:  
116,507 
 
Initial Protocol Version Date: 28AUG2012 
Amendment 1: 17OCT2012 
Amendment 2: 13JUN2013 
Amendment 3: 09JUL2014 
 


 
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Co-Investigators  
 
 
Indiana  
Costantine Albany, MD 
Oncology 
(317) 274-0843 
calbany@iu.edu 
University Melvin 
and Bren Simon  Nagendra Prasad, PhD 
Therapeutic 
Validation Core 
(317) 278-6608 
nkprasad@iupui.edu 
Cancer Center 
George Sandusky, DVM, PhD 
IHC Core 
(317) 278-2304 
gsandusk@iupui.edu 
 
Liang Cheng, MD 
Pathology 
(317) 491-6442 
lcheng@iupui.edu 
 
David Jones, PhD 
Clinical 
Pharmacology 
Analytical Core 
(317) 630-8727 
drjones1@iupui.edu 
 
Bryan P. Schneider, MD 
Oncology and 
Clinical 
Pharmacology 
(317) 944-0920 
bpschnei@iupui.edu 
 
Richard Bihrle, MD 
Urology 
(317) 278-9300 
rhbihrle@iupui.edu 
 
Michael Koch, MD 
Urology 
(317) 274-7338 
miokoch@iupui.edu 
 
Tom Gardner, MD 
Urology 
(317) 278-3434 
thagardn@iupui.edu 
 
Richard S. Foster, MD 
Urology 
(317) 274-3458 
rsfoster@iupui.edu 
 
Chandru Sundaram, MD 
Urology 
(317) 278-3098 
sundaram@iupui.edu 
Fox Chase   
Cancer Center 
Richard E. Greenberg, MD 
Urology 
(215) 728-5341 
richard.greenberg@fccc.edu 
Elizabeth Plimack, MD 
Oncology 
(215) 728-3889 
elizabeth.plimack@fccc.edu 
Dartmouth 
Hitchcock 
Medical Center 
Gregory J. Tsongalis, PhD 
Pathology 
(603) 650-5498 
gregory.j.tsongalis@hitchcock.org 
The Sidney 
Kimmel 
Emmanuel Antonarakis, MD 
Oncology 
(443) 287-0553 
eantona1@jhmi.edu 
Comprehensive 
Cancer 
Michael Carducci, MD 
Oncology 
(410) 614-3977 
carducci@jhmi.edu 
Center at Johns 
Hopkins 
Samuel Denmeade, MD 
Oncology 
(410) 955-8875 
denmesa@jhmi.edu 
 
Mario Eisenberger, MD 
Oncology 
(410) 614-3511 
eisenma@jhmi.edu 
 
Hans Hammers, MD, PhD 
Oncology 
(410) 502-1036 
hhammer2@jhmi.edu 
 
Jenny Kim, MD 
Oncology 
(410) 502-1036 
jkim366@jhmi.edu 
 
Trinity Bivalacqua, MD, PhD 
Urology 
(443) 287-0385 
tbivala1@jhmi.edu 
 
 
 


 
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PROTOCOL SIGNATURE PAGE  
 
Protocol title: Phase II Trial of Dovitinib in BCG-Refractory Urothelial Carcinoma Patients with Tumor 
FGFR3 Mutations or Over-expression: Hoosier Cancer Research Network GU12-157 
 
VERSION DATE:  09JUL2014 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the ethical 
principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for good clinical 
practices, or the applicable laws and regulations of the country of the study site for which I am responsible, 
whichever provides the greater protection of the individual.  I will accept the monitor’s overseeing of the study.  
I will promptly submit the protocol to applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Investigator                 Date 
 
 
____________________________________ 
 Investigator Name (printed) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL COPY TO HOOSIER CANCER RESEARCH NETWORK 
 
 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to Hoosier Cancer Research Network and keep a record 
for your files. 
 


 
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STUDY SYNOPSIS 
 
TITLE 
Phase II Trial of Dovitinib in BCG-Refractory Urothelial Carcinoma Patients with 
Tumor FGFR3 Mutations or Over-expression 
STUDY PHASE  
Phase II 
OBJECTIVES 
Primary Objective: 
 To determine the 6-month complete response rate in BCG-refractory UC patients 
with FGFR3 mutant or over-expressing tumors treated with dovitinib. 
 
Secondary Objectives: 
 To determine the 1-year relapse free survival (RFS) rate in BCG-refractory UC 
patients treated with dovitinib. 
 To determine the rate of progression to muscle-invasive stage (i.e. T2-T4). 
 To determine 3- and 6-month partial response rate defined as a reduction in T-stage 
on post-therapy TURBT (i.e. T1 ≥ Ta; T1+Tis ≥ Tis) 
 To characterize treatment related toxicity rates assessed by CTCAE v4.0 
Exploratory Objectives: 
 To characterize concordance rates between UC patient detected tumor, urine, and 
circulating free plasma FGFR3 mutations. 
 To characterize associations between pre-treatment germline (as assessed by 
PBMC extracted DNA) FGFR SNPs and post-treatment 6-month complete 
response rate and 1-year relapse free survival rate in patients treated with dovitinib. 
 To characterize associations between pre-treatment germline (as assessed by 
PBMC extracted DNA) VEGFR SNPs and post-treatment 6-month complete 
response rate and 1-year relapse free survival rate in patients treated with dovitinib. 
 To characterize VEGFR over-expression status within tumor tissue 
 To characterize pre- and post-treatment bladder tumor FGFR and VEGFR pathway 
phosphorylation  changes as  assessed  by  bladder  tumor  tissue 
immunohistochemistry. 
 To characterize post-treatment bladder tissue dovitinib concentrations. 
 To characterize associations between post-treatment hypertension, 6-month 
complete response rate and 1-year relapse free survival rate in patients treated with 
dovitinib. 
 
STUDY DESIGN 
This trial will be a single-arm, multi-center, phase II study conducted through Hoosier 
Cancer Research Network assessing the 6-month complete response rate and toxicity 
profile of oral dovitinib therapy in BCG-refractory urothelial carcinoma patients with 
tumors with FGFR3 mutations or over-expression who are ineligible for or refusing 
cystectomy.   
 
 
 


 
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NUMBER OF 
PATIENTS 
 
Screen 50 for 20 evaluable patients 
ELIGIBILITY 
Inclusion 
1. Histologically confirmed non-muscle invasive urothelial carcinoma of the bladder 
(NMIBC) defined as Ta, T1, or Tis stage.  Tumor staging must be confirmed by 
TURBT performed within 42 days prior to registration. 
2. Presence of either an FGFR3 mutation or FGFR3 over-expression within bladder 
tumor tissue.  FGFR3 mutations (see Table 1-2) in exons 7, 10, and 15 will be 
assessed by massively parallel sequencing analysis utilizing the Ion Torrent 
Personal Genome Machine (PGM) in the CLIA-certified Molecular Pathology and 
Translational Research Laboratory at the Dartmouth Hitchcock Medical Center .  
FGFR3 over-expression will be assessed by standard IHC analysis performed 
within the Indiana University Simon Cancer Center Immunohistochemistry (IHC) 
Core Lab.   
NOTE:  Patients will initially be allowed to enroll if their tumors demonstrate either 
an FGFR3 mutation or FGFR3 over-expression.  However, a minimum of 10 
FGFR3 mutation positive patients will be enrolled at study completion.  If 10 
patients with tumors that are FGFR3 over-expressors but FGFR3 mutation negative 
are accrued prior to enrolling 10 FGFR3 mutation positive patients, subsequent 
enrollment will be restricted to patients with tumors that are FGFR3 mutation 
positive. 
3. Documented BCG-refractory disease defined as failure to achieve a tumor free state 
after at least 2 prior intravesical treatment courses, one of which must have been 
intravesical BCG therapy.   
NOTE: There is no maximum limit on the number of prior BCG therapy courses.  
In addition, there is no maximum limit on the number of prior non-BCG 
intravesical therapy courses (i.e. gemcitabine, valrubicin, interferon, mitomycin C, 
etc.). 
4. Medically unfit to undergo cystectomy or electively choosing to forego cystectomy 
5. ECOG (WHO) performance status 0 or 1 or 2 
6. Age ≥ 18 years old 
7. Patients must have the following laboratory values: 
 White blood cell count (WBC) > 3.0 K/mm3 
 Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
 Platelets ≥ 100 K/mm3 
 Hemoglobin (Hgb) ≥ 9 g/dL 
 Serum total bilirubin: ≤ 1.5 x ULN 
 ALT and AST ≤ 3.0 x ULN 
 Serum creatinine ≤ 1.5 x ULN or serum creatinine > 1.5 – 3 x ULN if calculated 
creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockcroft-Gault equation, see 
formula below: 
CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] 
(if patient is female multiply the above by 0.85) 
 Urine dipstick reading: Negative for proteinuria or, if documentation of +1 (+2 for 
patients with renal cell carcinoma) results for protein on dipstick reading, then total 


 
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urinary protein ≤ 500 mg and measured creatinine clearance ≥ 50 mL/min/1.73m2 
from a 24 hour urine collection  
 
8. Patients who give a written informed consent obtained according to local guidelines 
 
Exclusion  
1. Patients with muscle-invasive (i.e. T2, T3, T4), locally advanced non-resectable, or 
metastatic urothelial carcinoma as assessed on baseline radiographic imaging 
obtained within 28 days prior to study registration.  The required radiographic 
imaging includes: 
a. Abdomen/Pelvis – CT scan 
b. Chest – chest x-ray or CT scan 
2. Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive 
urothelial carcinoma.   
3. Patients with another primary malignancy within 3 years prior to starting study 
drug, with the exception of adequately treated in-situ carcinoma of the uterine 
cervix, clinically localized prostate cancer, biochemically relapsed non-metastatic 
prostate cancer (i.e. PSA only disease), or skin cancer (such as basal cell carcinoma, 
squamous cell carcinoma, or non-melanomatous skin cancer) 
4. Patients who have received the last administration of an anti-cancer therapy 
including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks 
prior to starting study drug, or who have not recovered from the side effects of such 
therapy 
5. Patients who have received prior VEGFR-targeted or FGFR-targeted agents (i.e. 
sunitinib, pazopanib, sorafenib, bevacizumab, axitinib, etc.).  
6. Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who 
have not recovered from radiotherapy toxicities 
7. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or 
intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting 
study drug, or patients who have had minor procedures (i.e. TURBT), percutaneous 
biopsies or placement of vascular access device ≤ 1 week prior to starting study 
drug,  or who have not recovered from side effects of such procedure or injury 
8. Patients with any of the following concurrent severe and/or uncontrolled medical 
conditions which could compromise participation in the study: 
 Impaired cardiac function or clinically significant cardiac diseases, including any of 
the following: 
a. History or presence of serious uncontrolled ventricular arrhythmias 
b. Clinically significant resting bradycardia 
c. LVEF assessed by 2-D echocardiogram (ECHO) <  50% or lower limit of normal 
(whichever is higher) or multiple gated acquisition scan (MUGA), < 45% or lower 
limit of normal (whichever is higher) 
d. Any of the following within 6 months prior to starting study drug: myocardial 
infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), 
Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient 
Ischemic Attack (TIA), Pulmonary Embolism (PE) 
e. Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm 


 
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Hg, with or without anti-hypertensive medication(s) 
 Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 
 Cirrhosis, chronic active hepatitis or chronic persistent hepatitis 
 Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is 
not mandatory)   
 Patients who are currently receiving anti-coagulation treatment with therapeutic 
doses of warfarin.  Full-dose anti-coagulation with low molecular weight heparin is 
permitted. 
 Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. 
active or uncontrolled infection, uncontrolled diabetes) that could cause 
unacceptable safety risks or compromise compliance with the protocol 
 
9.  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test. 
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
(defined below). Highly effective contraception must be used by both sexes (female 
patients and their male partners) during study treatment and for 30 days after the 
last dose of study medication.  
 Highly effective contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment 
 Combination of the following (a+b): 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository  
Oral, implantable, or injectable hormone contraceptives may be affected by 
cytochrome P450 interactions, and are therefore not considered effective for this 
study 
Women of child-bearing potential (sexually mature women) who have not 
undergone a hysterectomy or who have not been naturally postmenopausal for at 
least 12 consecutive months (i.e., who has had menses any time in the preceding 12 
consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to 
starting study drug. 
11. Fertile males not willing to use contraception. Fertile males must use condom with 
spermicide. Highly effective contraception, as defined above, must be used by both 
sexes (male patients and their female partners) during study treatment and for 90 


 
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days after the last dose of study medication and should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to 
prevent delivery of the drug via seminal fluid.   
12.  Patients unwilling or unable to comply with the protocol 
 
EVALUATION 
CRITERIA 
Primary Objective:  
 The 6-month complete response rate is defined as the proportion of patients 
treated with dovitinib with no evidence of any remaining urothelial 
carcinoma tumors of any T-stage (including Tis) present within the bladder 
as assessed by standard of care cystoscopic examination with TURBT and 
urine cytology performed at 6 months after initiation of study therapy.   
Endpoints for Secondary Objectives: 
 The 1-year relapse free survival rate is defined as the proportion of patients 
treated with dovitinib with no evidence of any remaining urothelial 
carcinoma tumors at 12 months of follow-up.   
 The rate of progression to muscle-invasive stage for dovitinib is defined as 
the proportion of patients with clinical or pathologic progression to muscle-
invasive stages (i.e. T2-T4) at any time point on study. 
 The 3- and 6-month partial response rates are defined as the proportion of 
patients treated with persistent but reduced T-stage tumors on post-therapy 
TURBT (i.e. T1 ≥ Ta; T1+Tis ≥ T1). 
 Treatment related toxicity rates will be assessed by CTCAE v4.0. 
NOTE: Patients with residual non-invasive UC tumors with no component of 
carcinoma in situ (i.e. Ta, T1) at 3-month cystoscopy and TURBT are not 
considered relapses and will be permitted to continue on dovitinib therapy.  If the 
subsequent 6-month cystoscopy/TURBT, and urine cytology shows no evidence of 
any remaining urothelial carcinoma in such patients, they will be considered a 
complete response.  Patients with any component of carcinoma in-situ (CIS) at 3-
month cystoscopy/TURBT will be considered relapses and will not continue on 
dovitinib therapy. Any non-invasive UC tumors (i.e. Ta, T1, Tis) at the 6-month or 
any subsequent cystoscopy/TURBT is considered relapsed disease.  Similarly 
progression to invasive UC tumors (T2-T4) at any time point is also considered 
relapsed disease and patients will not continue on dovitinib therapy. 
Endpoints for Exploratory Objectives 
 Pre- and post-treatment bladder tumor FGFR pathway phosphorylation 
changes will be assessed by bladder tumor tissue immunohistochemistry 
utilizing commercially available antibodies including, but not limited to, the 
following:  FGFR3, pFGFR3, VEGFR2, pVEGFR2, FRS2, pFRS2, ERK, 
pERK.   
 Pre-treatment germline FGFR SNPs will be assessed by testing extracted 
DNA from patient PBMC’s (collected prior to initiating dovitinib therapy) 
with validated commercial probes. 


 
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 Pre- and post-treatment bladder tumor VEGFR pathway phosphorylation 
changes will be assessed by bladder tumor tissue immunohistochemistry 
utilizing commercially available antibodies including, but not limited to, the 
following:  FGFR3, pFGFR3, VEGFR2, pVEGFR2, FRS2, pFRS2, ERK, 
pERK. 
 Pre-treatment germline VEGFR SNPs will be assessed by testing extracted 
DNA from patient PBMC’s (collected prior to initiating dovitinib therapy) 
with validated commercial probes. 
 Presence of VEGFR over-expression within tumor tissue will be assessed and 
interpreted by standard immunohistochemistry analysis with appropriate 
controls. 
 Hypertension will be defined as a systolic blood pressure (SBP) of ≥ 140 
mmHg or a diastolic blood pressure (DBP) of ≥ 90 mm Hg recorded at any 
time after dovitinib therapy is initiated. 
 Presence of FGFR3 mutations (see Table 1-2) within patient tumor tissue and 
urine will be assessed by massively parallel sequencing of exons 7, 10, and 
15 utilizing the Ion Torrent PGM instrument. 
 Presence of FGFR3 mutations within patient free plasma will be assessed by 
PCR-amplification of the target regions and sequencing. 
 Post-treatment bladder tissue dovitinib concentrations will be assessed by 
TURBT fresh frozen tissue obtained at the 3-month cystoscopy  
STATISTICAL 
CONSIDERATIONS 
 
General Considerations  
Statistical analysis of this study will be the responsibility of the Department of 
Biostatistics at IUSM. Parameter estimates and relevant summary statistics will be 
reported for both efficacy and safety outcomes. Continuous variables will be 
summarized by means, medians, minima, maxima and standard deviations. Categorical 
variables will be summarized by frequencies and percentages. Missing data are expected 
to be rare. For patients that start therapy but do not make it to the primary endpoint 
evaluation, their 6-month status will be treated as not achieving CR. Consequently, our 
estimate of 6-month CR rate will be conservative. For secondary outcomes, missing 
data, if any, will not be imputed and complete-case analysis will be adopted. Additional 
exploratory analysis will be conducted when appropriate. Changes from the analysis 
plan will not require an amendment to the protocol unless it changes a significant feature 
in the protocol.  
Primary Objective Statistical Considerations  
The 6-month complete response rate will be summarized by frequency and rate.  The 
one-sided 90% confidence interval (CI) of Agresti-Coull type will be calculated for the 
rate.   
Secondary Objectives Statistical Considerations  
All secondary objectives are hypothesis generating in nature.  One year RFS will be 
summarized by mean, median and standard deviation.  Muscle-invasive progression, 3- 


 
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and 6-month PR, and toxicity rates will be presented as rates and corresponding 90% 
Agresti-Coull CIs.   
Sample size justification 
A one-sided 90% confidence interval (CI) of Agresti-Coull type will be calculated for 
the 6-month CR rate. With an expected CR rate of ≥ 25%, a sample size of 20 subjects 
will have a power of 0.80 to exclude a lower bound being ≤ 10%. 
ENROLLMENT 
PERIOD 
18 months 
FOLLOW-UP 
PERIOD 
6 months 
 
 
 


 
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Table of Contents 
Table of Contents 
...............................................................................................................11 
List of Appendices 
.............................................................................................................15 
List of Figures 
....................................................................................................................15 
List of Tables 
.....................................................................................................................15 
List of Abbreviations 
.........................................................................................................16 
Glossary of Terms 
..............................................................................................................19 
1. Background 
........................................................................................................................21 
1.1 Overview of Non-Muscle Invasive Urothelial Carcinoma of the Bladder 
(NMIBC) and Current Treatment Options for BCG-Refractory Patients 
..............21 
1.1.1 Non-Muscle Invasive Urothelial Carcinoma of the Bladder (NMIBC) 
.................21 
1.1.2 Intravesical Bacillus Calmette-Guerin (BCG) for High-risk Non-Muscle 
Invasive UC of the Bladder (NMIBC) 
...................................................................21 
1.1.3 Clinical Challenges of Post-BCG Tumor Recurrences 
..........................................21 
1.1.4 Non-surgical Approaches to Treating BCG-Refractory UC patients 
....................22 
1.1.5 Vascular Endothelial Growth Factor (VEGF) as a Therapeutic Target in UC 
......23 
1.1.6 Fibroblast Growth Factor Receptor as a Therapeutic Target in UC 
......................23 
1.2 Overview of Dovitinib 
...........................................................................................25 
1.2.1 
Mechanism of Action 
............................................................................26 
1.2.2 
Clinical Experience ...............................................................................26 
1.2.3 
Biomarker Development .......................................................................31 
2 Study Purpose/Rationale 
....................................................................................................32 
3 Objectives and Endpoints ..................................................................................................32 
3.1 Primary Objectives 
.................................................................................................32 
3.1.1 Endpoint for Primary Objectives 
...........................................................................32 
3.2 Secondary Objectives 
.............................................................................................33 
3.2.1 Endpoint for Secondary Objectives 
.......................................................................33 
3.3 Exploratory Objectives ..........................................................................................33 
3.3.1 Endpoint for Exploratory Objectives 
.....................................................................34 
4 Investigational Plan 
............................................................................................................37 
4.1 Study Design 
..........................................................................................................37 
4.1.1 
Investigational Treatment, Other Study Treatment, Study Treatment, 
Supportive Treatment 
............................................................................37 
4.1.2 
Treatment Arms 
.....................................................................................38 
4.2 Definition of End of the Study 
...............................................................................38 
4.3 Early Study Termination 
........................................................................................38 
5 Population 
..........................................................................................................................38 
5.1 Inclusion Criteria ...................................................................................................38 


 
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5.2 Exclusion Criteria ..................................................................................................39 
6 Treatment 
...........................................................................................................................41 
6.1 Treating the Patient 
................................................................................................41 
6.1.1 
Administration 
.......................................................................................41 
6.1.2 
Dosing and Treatment Schedule 
............................................................43 
6.1.3 
Dose Modification and Dose Delay ......................................................43 
6.1.4 
Treatment Interruption and Treatment Discontinuation 
........................43 
6.1.5 
Permitted Concomitant Therapy ...........................................................47 
6.1.6 
Prohibited Concomitant Therapy ..........................................................47 
6.1.7 
Hormonal Contraception Excluded 
.......................................................47 
6.2 Study Drug(s) 
.........................................................................................................47 
6.2.1 
Packaging and Labeling ........................................................................47 
6.2.2 
Supply, Receipt and Storage .................................................................47 
6.2.3 
Dispensing and Preparation 
...................................................................48 
6.2.4 
Drug Compliance and Accountability 
...................................................48 
6.2.5 
Disposal and Destruction 
.......................................................................48 
6.2.6 
Other Concomitant medication .............................................................48 
6.2.7 
Pharmacokinetic Interactions 
................................................................49 
7 Visit schedule and assessments 
..........................................................................................50 
7.1 Study Flow and Visit Schedule 
..............................................................................50 
7.2 Biomarkers 
.............................................................................................................56 
7.3 Eligibility Screening and Patient Registration 
.......................................................56 
7.4 Information Collected on Screen Failures .............................................................56 
7.5 Patient Demographics and Other Baseline Characteristics 
....................................56 
7.6 Treatment Period 
....................................................................................................58 
7.7 End of Treatment and Premature Withdrawal Visit ..............................................58 
7.7.1 
Criteria for Premature Patient Withdrawal 
............................................59 
7.7.2 
Follow-up for Toxicities 
........................................................................59 
7.8 Replacement Policy ...............................................................................................59 
7.9 Follow up Period 
....................................................................................................59 
7.10 Assessment Types 
..................................................................................................60 
7.10.1 Demographics 
........................................................................................60 
7.10.2 Diagnosis and Extent of Cancer 
............................................................60 
7.10.3 Prior Anti-neoplastic Therapy 
...............................................................61 
7.10.4 Vital Signs 
.............................................................................................61 
7.10.5 ECOG Performance Status 
....................................................................61 
7.10.6 FGFR1, FGFR2, FGFR3, VEGFR1, VEGFR2, and VEGFR3 Mutation, 
Over-expression, and Pathway Analyses ..............................................62 


 
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7.10.7 Cystoscopy, TURBT, and Urine Cytology Evaluations 
........................64 
7.10.8 Radiographic Evaluations 
......................................................................65 
7.10.9 Cardiac Evaluations 
...............................................................................66 
7.10.10 Correlative Studies 
................................................................................66 
7.10.11 Laboratory Studies ................................................................................67 
7.10.12 Efficacy .................................................................................................68 
7.10.13 Safety and Tolerability 
..........................................................................70 
8 Safety Monitoring and Reporting 
......................................................................................70 
8.1 Adverse Events ......................................................................................................70 
8.1.1 
Definitions and Reporting 
.....................................................................70 
8.1.2 
IND Safety Reports Unrelated to This Trial .........................................71 
8.1.3 
Laboratory Test Abnormalities .............................................................71 
8.2 Serious Adverse Events .........................................................................................72 
8.2.1 
Definitions 
.............................................................................................72 
8.2.2 
Reporting 
...............................................................................................72 
8.3 Pregnancies 
............................................................................................................74 
8.4 Warnings and Precautions 
......................................................................................75 
8.5 Data and Safety Monitoring Plan 
...........................................................................75 
9 Data Review and Management 
..........................................................................................75 
9.1 Data Confidentiality 
...............................................................................................75 
9.2 Site Monitoring 
......................................................................................................76 
9.3 Data Handling and Record Collection 
...................................................................76 
9.3.1 
Case Report Forms 
................................................................................76 
9.4 Database Management and Quality Control 
..........................................................76 
10 Statistical Methods and Data Analysis ..............................................................................77 
10.1 General Considerations 
..........................................................................................77 
10.2 Analysis Sets 
..........................................................................................................77 
10.2.1 Full Analysis Set ...................................................................................77 
10.2.2 Safety Set 
...............................................................................................77 
10.2.3 Per-Protocol Set 
.....................................................................................77 
10.2.4 Pharmacokinetic Analysis Set 
...............................................................78 
10.2.5 Efficacy Set ...........................................................................................78 
10.2.6 Other Analysis Sets 
...............................................................................78 
10.3 Patient Demographics/Other Baseline Characteristics ..........................................78 
10.4 Treatments (Study Drug, Concomitant Therapies, Compliance) 
...........................78 
10.4.1 Treatment Drug and Compliance 
..........................................................78 
10.4.2 Concomitant Therapies 
..........................................................................78 


 
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10.5 Primary Objective 
..................................................................................................78 
10.5.1 Primary Objective Statistical Considerations 
........................................78 
10.6 Secondary Objectives 
.............................................................................................78 
10.6.1 Key Secondary Objective(s) 
..................................................................78 
10.6.2 Secondary Objectives Statistical Considerations 
..................................79 
10.6.3 Safety Objectives 
...................................................................................79 
10.7 Exploratory Objectives ..........................................................................................80 
10.7.1 Exploratory Objectives Statistical Hypothesis, Model, and Method of 
Analysis 
.................................................................................................81 
10.8 Sample Size Calculation 
........................................................................................81 
10.9 Early Stopping Rules .............................................................................................81 
11 Ethical Considerations and Administrative Procedures.....................................................82 
11.1 Regulatory and Ethical Compliance 
......................................................................82 
11.2 Responsibilities of the Investigator and IRB/IEC/REB 
.........................................82 
11.3 Informed Consent Procedures 
................................................................................82 
11.4 Discontinuation of the Study .................................................................................83 
11.5 Publication of Study Protocol and Results 
.............................................................83 
11.6 Study Documentation, Record Keeping, and Retention of Documents 
.................83 
11.7 Confidentiality of Study Documents, and Patient Records ...................................83 
11.8 Audits and Inspections 
...........................................................................................83 
11.9 Financial Disclosures 
.............................................................................................84 
12 Protocol Adherence 
............................................................................................................84 
12.1 Amendments to the Protocol 
..................................................................................84 
13 References 
..........................................................................................................................85 
 
 


 
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List of Appendices  
None 
List of Figures 
Figure ‎
4-1 
Study design 
..........................................................................................37 
List of Tables 
Table 1-1     FGFR3 mutation and Over-expression Status   …………………........24 
Table 1-2    FGFR3 mutations to be analyzed using PGM ………………………..24 
Table 3-1 
Objectives and related endpoints 
...........................................................34 
Table 4-1 
Study drugs 
............................................................................................37 
Table 6-1 
Dosing and treatment schedule 
..............................................................41 
Table 6-2 
Dose reduction steps for dovitinib 
.........................................................41 
Table 7-1 
Visit evaluation schedule 
.......................................................................50 
Table 7-2 
Laboratory assessment schedule............................................................53 
 
 


 
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List of Abbreviations 
  
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ASCO 
American society of clinical oncology 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical therapeutic chemical classification system 
AUC 
Area under the curve 
BCG 
Bacillus Calmette-Guerin 
bFGF 
Basic fibroblast growth factor 
b.i.d. 
bis in diem/twice a day 
BP 
Blood pressure 
BSC 
Best supportive care 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
CBC  
Complete blood count 
CHF 
Congestive heart failure 
CI 
Confidence interval 
c-Kit 
Cellular kit tyrosine kinase receptor 
Cmax 
Maximum (peak) concentration of drug 
CML 
Chronic myeloid leukemia 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CK-MB 
MB isoenzyme of creatine phosphokinase 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper  
CRO 
Contract research organization 
CSF-1R 
Colony-stimulating factor-1 receptor 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR 
CT 
Computer tomography 
CTCAE 
Common terminology criteria for adverse events 
CTH 
Clinical Trial Head 
CVA 
Cerebrovascular accident 
CYP 
Cytochrome P 
DBP 
Diastolic blood pressure 
DCE-MRI 
Dynamic contrast-enhanced magnetic resonance imaging 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 


 
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ECHO  
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case record/report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EORTC QLQ-C30 The European Organisation for Research and Treatment Of Cancer Quality of Life 
Questionnaire QLQ-C30 
EOT 
End of treatment 
FAS 
Full analysis set 
FGF 
Fibroblast growth factor 
FGFR 
Fibroblast growth factor receptor 
FKSI-DRS 
Functional assessment of cancer therapy Kidney symptom index – Disease related 
symptoms 
FLT3 
FMS-like tyrosine kinase 3 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
GIST 
Gastrointestinal stromal tumor 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMS 
Integrated Medical Safety 
IN 
Investigator notification 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System  
ITT 
Intent-to-treat 
IV 
intravenous(ly) 
IVRS/IWRS 
Interactive voice response system/Interactive web response system 
LDL 
Low density lipoprotein 
LVEF 
Left ventricular ejection fraction 
MAP 
Master Analysis Plan documents project standards in the statistical methods, which will be 
used within the individual clinical trial RAP documentation. 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
mRCC 
Metastatic renal cell cancer/carcinoma 
MRI  
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multiple gated acquisition (scan) 
NCI  
National cancer institute 
NMIBC 
Non-muscle Invasive Bladder Cancer 


 
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o.d. 
omnia die/once a day 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD 
Pharmacodynamic 
PDGFRβ 
Beta-type platelet-derived growth factor receptor 
PE 
Pulmonary embolism 
pERK 
Phosphorylated extracellular signal-related kinase 
pFRS2 
Phosphorylated factor receptor substrate-2 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PLGF 
Placental growth factor 
p.o. 
per os/by mouth/orally 
PPS 
Per protocol set 
PR 
Partial response 
PRO 
Patient-reported outcome 
QOL 
Quality of life 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
RCC 
Renal cell cancer 
REB 
Research Ethics Board 
RECIST 
Response evaluation criteria in solid tumors 
RTK 
Receptor tyrosine kinase 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
SCF 
Stem cell factor 
SD 
Stable Disease 
SEC 
Study evaluation completion 
SGOT 
Serum glutamic oxaloacetic transaminase/AST 
SGPT 
Serum glutamic pyruvic transaminase/ALT 
SOP 
Standard Operating Procedure 
SSC 
Study steering committee 
SUSAR 
Suspected unexpected serious adverse reaction 
TIA 
Transient ischemic attack 
TKI 
Tyrosine kinase inhibitor 
TrkA 
Tyrosine kinase A receptor 
TSH 
Thyroid stimulating hormone 
TURBT 
transurethral resection of bladder tumor 
ULN 
Upper limit of normal 
UNE 
Upper limit not estimable 
UPC 
Urine protein/creatinine ratio 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WHO 
World health organization 


 
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Glossary of Terms 
 
SCHEMA 
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve blinding of investigational 
drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as number of days 
(e.g.: q28 days) 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent must be obtained (i.e. 
prior to starting any of the procedures described in the protocol) 
Investigational drug 
The study drug whose properties are being tested in the study; this definition is consistent with US 
CFR 21 Section 312.3 and is synonymous with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being testing in the study as well as their associated placebo and active 
treatment controls (when applicable).  This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as concomitant background therapy 
required or allowed by the protocol when used in within approved indication/dosage 
Other study treatment 
Any drug administered to the patient as part of the required study procedures that was not included 
in the investigational treatment 
Patient number 
A number assigned to each patient who enrolls in the study. When combined with the center 
number, a unique identifier is created for each patient in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional segments such as 
screening, baseline, titration, washout, etc. 
Premature patient withdrawal Point/time when the patient exits from the study prior to the planned completion of all study drug 
administration and assessments; at this time all study drug administration is discontinued and no 
further assessments are planned, unless the patient will be followed for progression and/or survival 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding to a specific treatment arm 
assignment 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major study milestones such as 
enrollment, randomization, completion of treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the tumor, whether lymph 
nodes contain cancer, and whether the cancer has spread from the original site to other parts of the 
body 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study drug was 
discontinued whichever is later 
Study drug 
Any drug administered to the patient as part of the required study procedures; includes 
investigational drug and any combination or control drug(s) 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the patient (subject) as 
part of the required study procedures, including placebo and active drug run-ins. 
In specific examples where it is important to judge study treatment relationship relative to a drug 
component of a combination treatment, study treatment in this case can refer to a drug component 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for any reason; may or may not also be 
the point/time of premature patient withdrawal 
 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data collected using specified 
assessments at specified time points 


 
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Phase II Trial of Dovitinib in BCG-Refractory Urothelial Carcinoma Patients with Tumor FGFR3 Mutations or 
Over-expression: Hoosier Cancer Research Network GU12-157 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Assessments 
o SOC Cystoscopy, urine cytology, TURBT q3month 
o CBC, CMP, toxicity assessment qMonth 
 Key Stats 
o The 6-month CR rate will be estimated with a one-sided 90% confidence interval of Agresti-
Coull type. With an expected CR rate of ≥ 25%, a sample size of 20 patients will have a 
power of 0.80 to exclude a lower bound being ≤ 10%. 
 Key Eligibility 
o Failure to achieve CR within 6 mo of initial BCG or recurrence within 12 mo of CR from 
prior BCG 
o FGFR3 mutation accessed by massively parallel sequencing analysis using the Ion Torrent 
PGM instrument or over-expression by IHC 
o Medically unfit to undergo cystectomy or willing to forego cystectomy 
o ECOG PS 0-2 
o No concurrent upper tract tumors 
 


 
 
 
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 Page 
1. Background  
1.1 Overview of Non-Muscle Invasive Urothelial Carcinoma of the Bladder (NMIBC) and 
Current Treatment Options for BCG-Refractory Patients 
1.1.1 Non-Muscle Invasive Urothelial Carcinoma of the Bladder (NMIBC) 
Currently, urothelial carcinoma (UC) of the bladder is the fifth most common site of new human cancer 
diagnoses.  In 2012, over 73,000 individuals will be diagnosed with UC, and more than 14,000 patients will die 
from their disease (Siegel et al., 2012).   Most new UC cases (~ 50,000 patients) are non-muscle invasive at 
diagnosis with disease limited to the mucosal epithelium (Ta/Tis) and immediate connective tissue layer 
beneath the mucosa (T1) (Ries et al., 2003).  The clinical course of non-muscle invasive UC of the bladder 
(NMIBC) is dominated by frequent recurrences and surveillance testing (cystoscopy, bladder biopsy, urine 
cytology, etc.).  The need for long-term invasive monitoring and treatment has significant cost and morbidity 
consequences for UC patients.  Compared to other malignancies, UC ranks highest in lifetime per patient costs 
with an average cost from diagnosis to death of $96,500 per patient (Botteman et al., 2003).   
High-risk NMIBC affects 25,000 patients each year and is defined by any carcinoma in-situ histology, T1 
tumors, grade 3 tumors, tumors  > 3 cm in size regardless of grade, greater than three tumors at presentation, 
and tumors that have recurred within 12 months of prior resection (Holmang et al., 1999, Pow-Sang and Seigne, 
2000).  Progression to muscle invasive stages requiring complete cystectomy for effective management occurs 
in 40% of high-risk NMIBC patients.  Progression to metastatic disease occurs in 20-30% of these individuals 
with death due to UC in nearly all of these patients (Cookson et al., 1997, Heney et al., 1983, Kurth et al., 1995, 
Millan-Rodriguez et al., 2000).   
 
1.1.2 Intravesical Bacillus Calmette-Guerin (BCG) for High-risk Non-Muscle Invasive 
UC of the Bladder (NMIBC) 
Standard therapy for high-risk NMIBC patients include transurethral resection of bladder tumor (TURBT) 
augmented by intravesical administration of Bacillus Calmette-Guerin (BCG).  BCG is a bovine mycoplasma 
derived agent which creates a profound inflammatory reaction in the bladder epithelium, and thereby, reduces 
tumor recurrences.  BCG therapy is typically administered on a weekly basis for six weeks via a urinary 
catheter which remains in the bladder for 2-3 hours during each administration.  The optimal length of BCG 
therapy beyond the six-week induction phase is unknown.  Two meta-analyses of randomized trials of TURBT 
+ BCG versus TURBT alone demonstrated a reduction in 12-month tumor recurrence rate from 56% to 29% 
(p<0.001) and a reduction in progression to muscle-invasive stages from 13.8% to 9.8% (p=0.001) in 
association with BCG therapy.  No improvement in overall survival was observed with the use of BCG therapy 
(Shelley et al., 2000, Sylvester et al., 2002).   
1.1.3 Clinical Challenges of Post-BCG Tumor Recurrences 
While BCG therapy is successful at preventing early tumor recurrences with 12-month post-BCG recurrence 
free survival rates approaching 70%, most patients do not maintain sustained remissions (Shelley et al., 2000).  
With 5-year follow-up, recurrent bladder tumors requiring repetitive TURBT and further cystoscopic 
surveillance are observed in 66% of patients (Herr, 2009).  For post-BCG UC tumor recurrences, a second six-
week course of BCG may be administered at the discretion of the treating urologist if a significant disease-free 


 
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interval was observed between the initial BCG instillation and the tumor recurrence.  Ultimately, however, 
failure of BCG to prevent tumor recurrences presents a significant clinical challenge in the management of 
NMIBC patients.   
Although a consensus definition is not established, UC patients with post-BCG recurrent tumors are generally 
classified as: 1) BCG-refractory – failure to achieve a tumor-free state by 6 months after initial BCG treatment; 
2) BCG-resistant – persistent tumor noted at 3 months after initial BCG treatment but to a lesser 
degree/stage/grade which clears by 6 months with additional BCG treatment; 3) BCG relapsing – recurrent 
tumor noted in follow-up after achieving a disease-free state at 6 months after initial BCG treatment; 4) BCG-
intolerant – recurrent tumor noted after a suboptimal initial BCG treatment which was truncated due to 
treatment related toxicity.  These definitions have important prognostic implications particularly in the BCG-
refractory population where 5-year rates of progression to muscle-invasive stage is observed in 58% of patients 
(Herr, 2009).    
1.1.4 Non-surgical Approaches to Treating BCG-Refractory UC patients 
Given the high-rate of progression to muscle-invasive stages, both the American Urological Association and the 
European Association of Urology have advocated for cystectomy as a standard option for BCG-refractory UC 
patients (2007, Babjuk et al., 2008).  However, due to the 28% morbidity and 3% mortality rates associated with 
cystectomy, many patients either have co-morbidities precluding surgical intervention or electively seek 
nonsurgical alternative therapy options (Stein et al., 2001).  Thus, a high interest and need exists to develop 
non-surgical alternative therapies for BCG-refractory UC patients. 
Additional intravesical therapy with non-BCG agents has been extensively evaluated both in the front-line and 
post-BCG settings.  Representative agents include mitomycin C, doxorubicin, gemcitabine, thiotepa, interferon-
alpha, docetaxel, and valrubicin.  In addition, newer technologies aimed at improving drug delivery such as 
local microwave hyperthermia and electromotive intravesical mitomycin C have been explored (O’Donnell and 
Boehle, 2006, Yates and Rouprêt, 2010).  Most often, however, trials have enrolled a mixture of BCG-
refractory and BCG -relapsing patients making between-study comparisons difficult. 
For true BCG-refractory UC patients, gemcitabine and valrubicin are the most thoroughly studied agents.  
Gemcitabine is a deoxycytidine analogue inhibitor of DNA synthesis with broad clinical activity in UC (El 
Karak and Flechon, 2007).  In a phase I study in BCG-refractory or BCG-intolerant UC patients, Dalbagni et al 
determined a maximum tolerated dose (MTD) of 2000 mg with intravesical gemcitabine administered twice 
weekly in 100 ml normal saline solution with a 1-hour bladder dwell time in three week cycles.  Treatment was 
well tolerated.  At the MTD, one of six patients had grade 3 thrombocytopenia and neutropenia in the absence 
of infection. Encouraging clinical activity was observed with 7 of 18 patients (39%) demonstrating a complete 
response (no tumor on bladder biopsy or urine cytology) (Dalbagni et al., 2002).  In a subsequent phase II study 
of intravesical gemcitabine administered according to the same phase I schedule at the 2000 mg dose and 
conducted in 30 BCG-refractory or BCG-intolerant patients, Dalbagni et al observed a complete response rate 
of 50% at the first post-gemcitabine cystoscopic examination with 30% of patients recurrence-free at 6-months.  
Only 3 patients (10%) maintained a complete remission for 12 months or longer.  At 1 year, the cumulative rate 
of progression to muscle-invasive stages was 3.5%.  Treatment continued to be well-tolerated with rare grade 3 
toxicities including: dysuria (20%), cellulitis (3%), rash (3%) (Dalbagni et al., 2006). 
Valrubicin is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline doxorubicin.  Valrubicin inhibits 
the breaking and resealing of DNA strands by topoisomerase II resulting in cell cycle arrest between S and G2 
phases (Onrust and Lamb, 1999).  In a phase I study in 32 patients eligible for intravesical therapy, 70% of 
whom had received prior BCG treatment, Greenberg et al determined an 800 mg intravesical MTD for 
valrubicin when administered weekly in a six week cycle with a 2-hour bladder dwell time.  Urinary symptoms 
including dysuria (53%), urinary frequency (32%), local urinary burning symptoms (28%), and hematuria 


 
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(22%) were the most commonly observed treatment related toxicities.  Complete response was observed in 13 
patients (41%) (Greenberg et al., 1997).  In a larger phase II study of intravesical valrubicin according to the 
phase I dose and schedule but restricted to a patient population of 90 BCG-refractory carcinoma in-situ UC 
patients, Steinberg et al observed a complete response rate at six months of 21% (19 patients).  Of the patients 
with complete response at six months, 13 maintained their response 12 months or greater duration for a 12-
month recurrence free rate of 14%.  Forty-four patients underwent cystectomy with 6 patients (7%) observed to 
have pathologic T3 or greater disease.  A toxicity profile similar to the phase I valrubicin experience was 
observed with urinary frequency (66%), urinary urgency (63%), and dysuria (60%) as the most commonly 
reported side effects.(Steinberg et al., 2000)  Based on these trial results, valrubicin was originally approved by 
the FDA for the treatment of BCG-refractory UC carcinoma in-situ patients in 1998 and later re-approved in 
May 2007 for the same indication after manufacturing quality concerns were addressed (2010b). 
Collectively, gemcitabine and valrubicin both demonstrate promising initial complete response rates in BCG-
refractory UC patients.  However, both agents produce durable remissions of greater than 1 year in only 10-15% 
of patients.  Therefore, a need clearly exists to explore the clinical efficacy of novel agents in this high-risk 
NMIBC population.  
1.1.5 Vascular Endothelial Growth Factor (VEGF) as a Therapeutic Target in UC 
The critical role of angiogenesis in migration, proliferation, and metastasis of malignant tumors is well 
established (Folkman, 1971, Folkman, 1975, Folkman, 1986, Folkman, 1995, Kerbel and Folkman, 2002).  
Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis.  In UC, investigators have 
demonstrated associations between tumor VEGF expression and prognosis (Fauconnet et al., 2009, Yang et al., 
2004).  Specifically, increased expression of the VEGF receptor has been associated with more advanced stage 
and tumor grade in UC patients (Swellam and El-Aal, 2005).  In preclinical UC models, the addition of anti-
angiogenic agents to platinum-based chemotherapy has shown improved tumor control (Kong et al., 2005, 
Sonpavde et al., 2009, Zhang et al., 2002).  In a phase II study in 77 post-platinum metastatic UC patients 
treated with the oral VEGF receptor tyrosine kinase inhibitor sunitinib, Gallagher et al observed a partial 
response rate of 5% (4 patients).  However, some tumor regression or stable disease lasting > 12 weeks was 
achieved in 43% of patients (Gallagher et al., 2010).  Similarly, Bellmunt et al examined the activity of sunitinib 
in 37 chemo-naive platinum-ineligible metastatic UC patients.  A partial response rate of 8% was observed with 
stable disease > 12 weeks in 54% for a clinical benefit rate of 62% (Bellmunt J et al., 2010).  In a phase II trial 
in 43 platinum-eligible front-line metastatic UC patients, Hahn et al observed a 72% response rate (19% 
complete response, 53% partial response) when the anti-VEGF-A receptor monoclonal antibody bevacizumab 
was added to standard cisplatin plus gemcitabine chemotherapy (Hahn NM et al., 2010).  A promising overall 
survival of 19.1 months was observed, however, high rates of toxicity were encountered with venous 
thromboembolic events in 21% of patients and 3 treatment related deaths (1 CNS hemorrhage, 1 aortic 
dissection, and 1 sudden cardiac death).  It is unclear if the toxicity observed in this study is a bevacizumab 
related phenomenon or a reflection of increased thromboembolic risk in metastatic UC patients undergoing 
cytotoxic chemotherapy as similar rates have been reported by other investigators in UC patients receiving 
chemotherapy in the absence of anti-angiogenic therapy (Apolo et al., 2009).  Taken together, these studies in 
advanced poor prognosis UC populations demonstrate promising anti-tumor activity with VEGF directed 
therapy.  Thus, a rationale exists for targeting VEGF in earlier stage UC patients. 
1.1.6 Fibroblast Growth Factor Receptor as a Therapeutic Target in UC 
UC carcinogenesis is a multi-step process that affects multiple cellular genes and signaling pathways.  Low-
grade NMIBC tumors are characterized by mutations in the fibroblast growth factor receptor-3 (FGFR3) and the 
Harvey rat sarcoma viral oncogene homologue (HRAS) genes (Mitra et al., 2006, Wu, 2005).  FGFR3 


 
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mutations or over-expression promote FGFR dimerization and constitutive activation of downstream signaling 
pathways in the absence of ligand in up to 80% of early-stage UC tumors (Table 1) (Knowles, 2008).   
 
Table 1-1: FGFR3 mutation and Over-expression Status According to T-stage 
 
Ta (%) T1 (%) T2 (%) 
Mutation 
67 
42 
13 
Over-expression 
13 
15 
39 
Total 
80 
57 
52 
 
While many FGFR3 mutations have been reported, S249C, Y375C, R248C, and G372C account for greater 
than 95% of all reported mutations (Kompier et al., 2010).  These mutations result in a hyperplastic phenotype 
dominated by frequent tumor recurrences with infrequent progression to muscle-invasive stages.  Somatic 
FGFR3 mutations (see Table 1-2) in exons 7, 10, and 15 will be assessed in FFPE tumor tissues by massively 
parallel sequencing analysis utilizing the Ion Torrent Personal Genome machine (PGM) and performed in the 
CLIA-certified Molecular Pathology and Translational Research Laboratory at the Dartmouth Hitchcock 
Medical Center. 
 
Table 1-2: FGFR3 mutations to be analyzed  
FGFR3 
Mutations 
R248C 
S249C 
G372C 
S373C 
Y375C 
K562E 
K562Q 
K562M 
K562T 
 
While FGFR3 mutations are highly associated with low-grade NMIBC, over-expression of FGFR3 has been 
observed in up to 42% of muscle-invasive UC tumors (Tomlinson et al., 2007).  Furthermore, either an FGFR3 
mutation or over-expression of the FGFR3 protein in the absence of mutation has been observed in 54% of 
muscle-invasive UC tumors (Tomlinson et al., 2007).  Thus, while FGFR3 mutations likely are an early event in 
the tumorigenesis of low-grade non-invasive UC tumors, over-expression of FGFR3 may still play a role in the 
continued proliferation of high-grade muscle-invasive UC tumors.  Furthermore, increasing evidence 
demonstrates that fibroblast growth factor receptor-1 (FGFR1) is a crucial mediator of tumor angiogenesis 
(Powers et al., 2000).  In preclinical tumor models, blockade of the FGF pathway has proven to be an effective 
method of overcoming resistance to VEGFR inhibitors (Casanovas et al., 2005).  Given the previously 
described importance of VEGF in UC progression, a rationale exists for combined VEGFR and FGFR 
inhibition in UC patients.  A combined VEGFR/FGFR approach may be particularly well suited for early-stage 
UC patients where both pathways play critical biological roles. 
 


 
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1.2 Overview of Dovitinib 
Dovitinib is an inhibitor of RTKs: FGFR, VEGFR, PDGFRβ, CSF 1R, c-Kit, RET, TrkA, and FLT3 that 
mediate tumor cell proliferation and survival. 
RTKs are involved in the growth of different types of tumors as well as in the initiation, growth, and 
maintenance of blood vessels supplying the tumor with blood, oxygen, and nutrients (Arteaga, 2001, Cohen, 
2002, Schlessinger, 2000). 
Several RTKs are expressed on solid tumors and are involved in cancer cell growth and survival (Collett and 
Erikson, 1978, Takahashi et al., 1995).  In some cases, mutations of these RTKs and their subsequent aberrant 
signaling are directly linked to the abnormal growth of tumor cells (Deininger et al., 2000, Mizuki et al., 2000).  
In many other cases, expression and/or over-expression of these RTKs have been demonstrated; however, the 
exact role of these kinases in tumorigenesis is still unknown.  It has been found that some tumors are dependent 
on a single mutation in a growth factor receptor kinase.  These include FLT3 mutations in 20% to 30% of 
patients with Acute Myeloid Leukemia (AML) (Gilliland and Griffin, 2002); FGFR3 ectopic 
expression/mutation in 15% to 20% of patients with multiple myeloma (Li et al., 2001, Rasmussen et al., 2003); 
c-Kit in gastrointestinal stromal tumors (GIST), a rare form of stomach cancer (DeMatteo, 2002), and the 
Philadelphia chromosome fused gene translocation mutation (Bcr-Abl) in nearly all patients with Chronic 
Myeloid Leukemia (CML) (Druker et al., 2001a, Druker et al., 2001b). 
RTKs such as VEGF receptors, FGF receptors, and PDGF receptors have been shown to play an important role 
in tumor angiogenesis (Dvorak, 2003).  VEGF is produced by both the host and the cancer cells and has a direct 
effect on endothelial cells, causing their proliferation, migration, invasion, and growth (Nagy et al., 2002).  
FGFs are potent stimulators of angiogenesis in both normal and pathological tissues, having a direct effect on 
both vessel assembly and sprouting (Auguste et al., 2003).  Blockade of the FGF pathway can overcome 
resistance to VEGFR inhibitors, emphasizing the importance of FGFR and specifically the need for multi-
targeted inhibitors (Casanovas et al., 2005).  PDGF receptors are expressed on pericytes - smooth muscle cells 
that surround the vasculature and provide maintenance and support to the tumor neo-vasculature (Bergers et al., 
2003).  Inhibition of these three growth factor receptor kinases should provide a powerful and broad inhibition 
of the angiogenesis process and provide potent anti-tumor effects. 
 
Dovitinib is a broad-targeted-profiled RTK inhibitor active against these three RTKs (VEGF, FGF and PDGF) 
involved in tumor cell growth.  Based on its potency as an inhibitor of these RTKs both in vitro and in vivo, and 
the compound’s oral availability, dovitinib has been investigated as a single agent in metastatic renal cell 
carcinoma (RCC), metastatic breast cancer (mBC), hepatocellular carcinoma (HCC), endometrial cancer, 
advanced urothelial cancer (mainly bladder cancer), advanced melanoma, multiple myeloma (MM), acute 
myeloid leukemia (AML), and other solid tumor studies. It is also being investigated in combination with 
fulvestrant in a metastic breast cancer study.  The maximum tolerated dose (MTD) of dovitinib was 400 mg/day 
for the continuous once daily dosing regimen and 500 mg/day for the 5 days on/2 days off dosing regimen. 
 
A comprehensive review of dovitinib is contained in the Investigator’s Brochure (IB) supplied by the 
investigational drug supplier, Novartis.  This document should be reviewed prior to initiating the study. 


 
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1.2.1 Mechanism of Action 
Dovitinib exhibits a dual mechanism of action: anti-tumor effects via its anti-proliferative activity as well as 
anti-angiogenic activity.  Dovitinib is a potent inhibitor in cells of the VEGFR 1, 2, and 3, FGFR1 (inhibitory 
concentration 50% (IC50 of 8nM), FGFR2 (IC50 of 40nM) and FGFR3 (IC50 of 9nM), PDGFRβ, c-Kit, RET, 
TrkA, CSF 1R, and FLT3 with IC50s of less than 40nM.  Stem cell factor (SCF) also termed KIT ligand, or 
steel factor has been shown to modulate tumor angiogenesis (Zhang et al., 2000).  In cultured human endothelial 
cells and c-Kit expressing cancer cells, dovitinib inhibited VEGF- and SCF-stimulated mitogenesis; in a second 
model of angiogenesis driven by FGF-2, dovitinib potently inhibited neovascularization of Matrigel plugs in 
vivo with an average effective dose (50% inhibition) (ED50) of 3 mg/kg.  The effects on endothelial cells 
suggest that dovitinib may have potent anti-angiogenic activity.  PDGFR and FGFR are also believed to play a 
role in the proliferation of certain tumor cells and supporting stromal cells.   
As a result of inhibition of target RTKs by dovitinib, other ligand-stimulated cellular functions are blocked, 
including activation of downstream signaling molecules, cellular proliferation, and survival.  Anti-tumor effects 
for this agent may therefore be secondary to anti-angiogenesis, anti-proliferative activity against tumor cells, 
and anti-stromal activity. 
1.2.2 Clinical Experience 
As of 10 September 2013, a total of 2078 patients have been treated across 45 dovitinib clinical trials; including 
approximately 1693 patients treated in 22 Oncology Clinical Development trials and 385 patients treated in 23 
investigator initiated clinical trials. 
Adverse events (AEs) and/or laboratory data (hematology and chemistry) were available from 1009 patients as 
of 10 September 2013. The five most commonly reported non-laboratory AEs were nausea, fatigue, diarrhea, 
vomiting and decreased appetite for both continuous daily dosing and 5 days on/2 days off dosing regimens. 
Commonly reported AEs were reversible and manageable; most were mild or moderate in severity (CTCAE 
grade 1 or 2). 
The majority of the hematology laboratory abnormalities were grade 1 or 2 events across all dosing regimens. 
Regarding ANC abnormalities, in the 5 days on/2 days off dosing regimen, there were 20 patients with grade 3 
and 5 patients with grade 4 absolute neutrophil count (ANC) decreases out of 455 patients in solid tumor and 
MM studies. In the Phase III RCC study, there were 5 patients with grade 3 and 2 patients with grade 4 platelet 
count decreases out of 269 patients evaluable for this parameter. Regarding platelet abnormalities, there were 16 
grade 3 and 5 with grade 4 platelet count decrease out of 465 patients in solid tumor and MMstudies . In the 
Phase III RCC study, there were 3 patients with grade 3 and 3 patients with grade 4 platelet count decrease out 
of 268. 
  The most frequent lab test abnormalities observed for biochemistry wereliver function test (LFT) elevations 
(aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, and total bilirubin). 
In most cases these changes were CTC grade 1 or 2. Below is a brief summary of the grade 3/4 LFT elevations 
for the 5 days on/2 days off dosing regimen as of 10 September 2013: 
 AST: 29 grade 3 and 1 grade 4 were reported out of 784 patients evaluable for this parameter. 
 ALT: 24 grade 3 and 2 grade 4 were reported out of 785 patients evaluable for this parameter. 
 Total bilirubin: 3 grade 3 and 4 grade 4 were reported out of 782 patients evaluable for this parameter. 
As of 30 June 2013, a total of 25 non-HCC patients who received dovitinib treatment had post-baseline LFT 
elevations defined astotal bilirubin > 2 x ULN and AST and/or ALT > 3 x ULN( including 1 patients whose 
LFT increase occurred more than 30 days after the last dose of dovitinib).  None of the  patients qualifies as a 


 
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“Hy’s Law” case (Reuben, 2004). Please see IB edition 12 Section 5.2.1.5 Hepatic dysfunction as defined by 
laboratory criteria for more detail.  
Two cases of hepatic disorders that were deemed dovitinib-related by the Investigator and 
resulted in death have been reported as of 10 November 2013. Please see IB edition 12 
Section 5.2.1.7Investigator notifications for more detail. 
 
 As reported in IB edition 12, baseline and on-study ECG data were available from 854 patients who were 
treated with TKI258 on the 5 days on / 2 days off schedule across 8 single agent studies, CTKI258A2107, 
CTKI258A2112, CTKI258A2116, CTKI258A2128, CTKI258A2201, CTKI258A2202, CTKI258A2204, and 
CTKI258A1101, and one randomized controlled study, CTKI258A2302. Consistent with the September 2009 
analyses, outlier analyses did not suggest an effect of dovitinib on the ECG intervals QTcF, PR, or QRS. The 
proportion of patients with post-baseline QTcF > 480 msec and QTcF > 500 msec were < 1% for each category; 
the proportion of patients with QTcF change from baseline > 60 msec also was < 1%. Similarly, proportion of 
patients with notable changes in QRS (increase from baseline > 25% and to a value > 110 msec) and PR 
(increase from baseline > 25% and to a value > 200 msec) was < 1% for each interval. 
As reported in IB edition 12, baseline and on-study cardiac imaging data were available from 527 patients 
treated with dovitinib across 13 studies: CTKI258A2101, CTKI258A2102, CTKI258A2103, CTKI258A2104, 
CTKI258A2105, CTKI258A2107, CTKI258A2112, CTKI258A2116, CTKI258A2128, CTKI258A2201, 
CTKI258A2202, CTKI258A2204, and CTKI258A2302. 
Of these 527 patients who had both baseline and on-study data, 20 patients (3.8%) had a post-treatment 
decrease in ejection fraction (EF) ≥ 20% on ECHO or MUGA. Among these 20 patients, 15 had EF decrease to 
a value that was below 50% (Table 5-24). The LVEF data and associated clinical data were reviewed by an 
independent cardiologist consultant. According to his assessment, dovitinib was probably or at least possibly 
contributory to the decrease in LVEF in 2 cases, based on the available data. 
 
 
As of the 28 April 2011 cutoff date, the median progression-free survival (95% CI) was 5.45 months (0.03 to 
10.68 months) and the median overall survival (95% CI) was 11.79 months (0.95 to 15.57 months) for the 59 
advanced RCC patients enrolled into the phase II portion of study CTKI258A2107. In the updated efficacy 
analysis of the Phase II portion of this study with data cutoff of 30 March 2012, 67 heavily pre-treated patients 
showed a median progression free survival of 3.7 (CI 3.0-5.6) months. Investigator assessment of median PFS 
was also 3.7 (CI 3.3-5.5) months with a median OS of 11.8 months. An overall median PFS of 3.7 months is 
considered to be clinically beneficial in this heavily pretreated population. In phase I clinical pharmacology 
solid tumor studies (CTKI258A2112 and 2116), the following tumor types have demonstrated clinical benefit 
(i.e., prolonged disease stabilization for at least 4 months or tumor regression): thyroid cancer, RCC, pancreatic 
neuroendocrine tumors, colon cancer, adnexal tumor, melanoma, gastrointestinal stromal tumor, prostate 
cancer, thymoma, and adenoid cystic carcinoma with FGFR1 amplification.  In addition, a confirmed partial 
response has been observed in one patient with advanced ovarian carcinoma (study 2112). 
As of September 2012, pharmacokinetic data was available from about 500 patients in phase I and II studies. 
Noncompartmental analysis was conducted on full plasma PK profiles of dovitinib. Coefficients of variation in 
the PK parameters (C
max and AUC
24) ranged from 16 to 111Cmax was observed at approximately 4-8 hours after 
dosing, and the concentration of dovitinib declined monoexponentially thereafter. Within the tested dose levels 
ranging from 50 to 600 mg/day, linear absorption of dovitinib was observed. Dovitinib was extensively 
distributed to tissues. 


 
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Time-dependent PK of dovitinib was observed across all tested dose levels ranging from 50 to 600 mg/day. 
Following multiple daily administration at doses below 400 mg, the auto-induction of CYP1A1/A2 resulted in 
lower plasma exposure of dovitinib on day 7 (steady state) than that observed on day 1. However, after 
increasing the daily dose to 400 - 600 mg, TKI258 plasma concentration on day 7 was found to be similar to or 
greater than that on day 1, suggesting a more pronounced accumulation of dovitinib at higher doses. In addition, 
an over-proportional increase in dovitinib plasma exposure was observed with doses from 400 to 600 mg/day. 
The maximum tolerated dose of dovitinib for the continuous daily dosing schedule was 400 mg (study 2105). 
The time-dependent PK and the nonlinear PK resulted in dose-dependent time to reach steady state, as well as 
dose-dependent accumulation at steady state. To prevent the prolonged and over-proportional accumulation in 
dovitinib exposure with dose escalation, an intermittent dosing schedule of 5 days on/2 days off was proposed 
for study 2107. At tested dose levels of 500 mg and 600 mg, no accumulation was observed on day 15 (steady 
state). The MTD for the 5 days on/2 days off dosing schedule was 500 mg (studies 2107 and 1101). 
A human ADME (absorption, distribution, metabolism and excretion) study identified the major metabolites of 
dovitinib as C-hydroxyl metabolites (in feces) and an N-oxide (in plasma). These metabolites are more than 5-
fold less pharmacologically active than the parent drug. The ADME study demonstrated that the majority of the 
dose administered was recovered from feces, and less than 21% of the dose was recovered in urine.  In addition, 
the oral absorption of dovitinib was ~75% of the dose (2106). 
Drug-drug interaction studies are ongoing. Available data from human, as well as in vitro studies, demonstrate 
that dovitinib has low or no inhibition potential for CYP450s. Therefore, dovitinib is not expected to cause 
inhibitory metabolic drug-drug interactions when co-administered with drugs metabolized by CYP450s. 
Dovitinib, however, does induce CYP1A2, CYP2C9 and CYP2C19; hence co-administration with substrates of 
CYP1A2/2C9/2C19 could reduce the exposure of these substrates. 
A relative bioavailability (BA) study (2112) was conducted to compare the final market image (FMI) capsule of 
dovitinib (monohydrate salt) with the clinical service form (CSF) capsule of dovitinib (anhydrate salt). PK data 
from 16 evaluable patients demonstrated that the FMI capsule and the CSF capsule have comparable 
bioavailability. Therefore, FMI capsules have replaced CSF capsules to be used in the clinical studies. 
Similarly, another relative bioavailability study (2116) is being conducted to compare the FMI tablet of 
dovitinib (monohydrate salt) with the CSF capsule of dovitinib (anhydrate salt).  PK data from the first 16 
evaluable patients demonstrated that the FMI tablet and CSF capsule have comparable bioavailability. 
Therefore, FMI tablets are being used in some new clinical studies moving forward. 
Tests of food effect (FE) on absorption of dovitinib FMI capsules demonstrated that there was no clinically 
relevant effect in humans (study 2112). Based on the results of the food effect test, dovitinib FMI capsules can 
be taken with or without food. 
Summary of potential toxicity in patients 
Gastrointestinal system 
Nausea, vomiting, anorexia/decreased appetite, and diarrhea were reported as DLTs in clinical studies with 
dovitinib. Additionally, they were the top commonly reported AEs for both continuous once daily dosing 
regimen (N = 155) and 5 days on/2 days off dosing regimen (N = 378 for global, N = 28 for Japan study 1101). 
Most of these events were mild to moderate (grade 1/2). Grade 3/4 events occurred in less than 10% of patients 
for both continuous once daily dosing regimen and 5 days on / 2 days off dosing regimen, with an exception of 
grade 3/4 decreased appetite reported in 14.3% of patients treated in the phase I study in Japan.. 


 
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Cases of gastrointestinal tract perforation and fistula formation with suspected relationship to the study drug 
have been reported. Dovitinib inhibits VEGF along with FGFR and PDGF; perforation and fistula formation is 
a known class effect for VEGF inhibitors.  
Cardiovascular system 
Sinus bradycardia and hypertensive crisis were reported as DLTs in clinical studies with dovitinib. Additionally, 
hypertension was the most commonly reported AE in the 14.3% of patients on 5 days on/2 days off dosing 
reschedule (N = 378, global studies). Hypertension is a well-known effect of VEGF inhibition. Patients should 
be monitored for blood pressure as per study protocol. In situations for which hypertension or worsening state is 
being reported, protocol toxicity management guideline should be followed. When needed, adequate medical 
care (e.g. anti-hypertensive therapy) should be administered according to the institutional standard practice. 
As QT prolongation has been reported in other tyrosine kinase inhibitors, an extensive ECG monitoring 
schedule has been implemented in 14 clinical studies with dovitinib. 
According to the central ECG analysis, available ECG data revealed no effect on cardiac repolarization of 
dovitinib across days and doses of therapy, nor is there any specific outlier signal observed consistent with the 
central tendency finding. This conclusion was also supported by a negative result in the exposure-ECG model. 
ECHO/MUGA evaluation was performed in 14 clinical studies with dovitinib (N = 517). The available data was 
reviewed by an independent cardiologist consultant, who concluded that, based on the available data; dovitinib 
probably or at least possibly contributed to a ≥ 20% increase in LVEF in 4 patients (0.8%). Nevertheless, please 
follow study protocol inclusion/exclusion criteria, and adhere to safety monitoring schedule for ECG, cardiac 
enzymes including troponin, creatine phosphokinase (CK) and MB isoenzyme of creatine phosphokinase (CK-
MB), and cardiac imaging (MUGA/ECHO). Toxicity management guideline as provided in the study protocol 
must be followed when a cardiac abnormality is observed. There is the need for extra caution to patients with 
history of QT interval prolongation and decreased LVEF. 
 
Hematologic events 
 
Neutropenia was reported as DLTs from dovitinib clinical studies (continuous once daily dosing regimen) in 
patients with acute myeloid leukemia or multiple myeloma.  
 
Grade 3 and 4 hematological toxicity is generally not common in patients treated with dovitinib for solid 
tumors. Grade 3 and 4 decrease in neutrophil values were observed in 3.6% and 1.5% of patients in the global 
Phase I and II studies, in 1.1% and 0.2% of patients in the global Phase III RCC study, in 3.4% and 0.0% of 
patients in the global Phase II HCC study and in 10.7% and 3.6% in the Japanese phase I study, respectively. 
Grade 3 and 4 thrombocytopenia is also uncommon, with grade 3 and 4 decrease in platelet values observed in 
3.3% and 0.6% of patients in the global Phase I and II studies, in 0.0% of patients in the global Phase III RCC 
study, in 8.1% and 1.3% of patients in the global Phase II HCC study, in 1.8% and 1.2% in the Phase I BE study 
and in 3.6% and 0.0% of patients, respectively in the Japanese phase I study. Additionally, grade 3/4 
lymphopenia was reported as an adverse event in 21.4% of patients in the Phase I Japan study (17.9% of grade 3 
and 3.6% of grade 4) (Table 5-16).  
 
Investigators are advised to follow protocol provided guidelines for hematologic toxicity management, e.g. dose 
modification, treatment interruption/discontinuation. 
Hepatic effects 


 
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Delayed recovery from AST/ALT elevations and grade 3 liver function disorder were reported as DLTs in 
dovitinib phase I clinical studies.  
 
Newly occurring or worsening grade 3 and 4 increase in AST values were observed in 5.6% 
and 0.3% of patients in the global Phase I and II studies, in 0.2% and 0.0% of patients in 
the global Phase III RCC study, in 26.2% and 1.3% of patients in the global Phase II HCC 
study, in 1.8% and 0.0% of patients in the Phase I BE study and in 14.3% and 0.0% of 
patients in the Japanese phase I study, respectively. Newly occurring or worsening grade 3 
and 4 increase in ALT values were observed in 5.3% and 0.5% of patients in the global 
Phase I and II studies, in 0.2% and 0.0% of patients in the global Phase III RCC study, in 
15.4% and 1.3% of patients in the global Phase II HCC study, in 0.0% of patients in the 
Phase I BE study and in 10.7% and 0.0%, respectively in the Japanese phase I study. 
ALT/AST increased as an adverse event, regardless of study drug relationship, were common 
in AST and ALT in the global Phase I and II studies; 3.1% and 2.6% of patients for AST and 
ALT, respectively, in the global Phase III RCC study; 1.8% and 0.6% of patients for AST 
and ALT, respectively, in the global Phase I BE study; 25.5% and 18.8% of patients for AST 
and ALT, respectively, in the global Phase II HCC study and 25 – 28.6% of patients in the 
Japan study) (Table 7-1, Table 7-2, Table 7-3, Table 7-4 and Table 7-5). In addition, 
grade 3/4 ALT/AST increased, regardless of study drug relationship, were reported in 2.4 – 
2.9%, 12.1 – 23.5%, and 3.6% for the 5 days on / 2 days off global Phase I and II studies, 
Phase II HCC study, and Phase I Japan study, respectively. Of note, no patients treated 
with dovitinib have experienced hepatotoxicity meeting the criteria for Hy’s Law, which 
is considered predictive of severe drug-related hepatocellular injury.   
In addition, a fatal case of hepatotoxicity (cholestatic liver injury) was observed in a patient with metastatic 
breast cancer after approximately one month of treatment with dovitinib; both the cholestatic liver injury and 
the death were deemed drug-related by the investigator. A review of the safety database for dovitinib showed 
that no other serious hepatotoxic event with a similar pattern and severity.  
Dovitinib inhibits VEGF, as well as FGFR and PDGF. Hepatotoxicity is a known class effect for VEGF 
inhibitors. Investigators are reminded to evaluate the pattern of liver function test abnormalities and follow the 
management paradigm in the study protocols to interrupt or discontinue dovitinib treatment. Dovitinib re-
challenge should only be considered if the patient’s liver function tests return to grade 1 or baseline. 
 
Renal system 
No DLTs were reported in the renal system in phase I studies. Grade 3 and 4 increase in creatinine values is not 
common in patients treated with dovitinib (1.6 and 0.8% of patients in the global Phase I and II studies; 0.0 and 
0.6% of patients in the Phase I BE study; 0.7 and 0.0% in the HCC study and no grade 3 or 4 creatinine value 
increase in the Japanese phase I and Phase III RCC studies.  
 
Other reported toxicities 
Increased gamma glutamyltransferase and hypokalemia were the other laboratory DLTs, whereas 
fatigue/asthenia were the other non-laboratory DLTs reported in. For both dosing schedules (once daily and 5 
days on/2 days off), fatigue/asthenia were listed among the commonly reported AEs (≥10% of patients). In 
addition, fatigue/asthenia had high incidences among all grade 3/4 events.  


 
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Other commonly reported adverse events from both dosing schedules, regardless of study drug relationship, 
include headache, dyspnea, constipation, pyrexia, cough, dyspepsia, and dry mouth. About 3.9% of patients (n = 
16) reported for palmar-plantar erythrodysesthesia syndrome (PPES) in the studies using 5 days on/2 days off 
dosing schedule (N = 378 global studies, and N = 28 Japan study 1101). Among them, 3 grade 3 events were 
reported and no grade 4 events were observed. PPES has also been reported with the use of other tyrosine 
kinase inhibitors. 
 
Serum amylase and triglycerides are monitored in the clinical studies with dovitinib, because their abnormal 
levels were reported in the preclinical toxicology studies. Newly occurring or worsening grade 3/4 increase in 
triglycerides were reported in patients who have received dovitinib treatment in clinical trials of the 5 days on/2 
days off dosing schedule; 88 with grade 3 and 18 with grade 4. 
1.2.3 Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biological processes, pathogenic 
processes and/or pharmacologic responses to a therapeutic intervention.  
In preclinical in vitro models in the RT114 and RT4 UC cell lines which over-express FGFR3, significant 
inhibition of FGFR3 signaling and cell growth was observed in association with dovitinib therapy.  
Furthermore, in an orthotopic model of FGFR3 S249C activating mutation transformed NIH3T3 fibroblast 
subcutaneous tumor implants, dovitinib significantly inhibited tumor growth.  In addition, dovitinib was well 
tolerated and demonstrated anti-tumor activity in an orthotopic bladder cancer mouse model in tumors over-
expressing FGFR3 (2010a).  The relative contributions of FGFR3 over-expression versus specific FGFR3 
activating mutations in human urothelial carcinoma have not been fully characterized.  Therefore as a secondary 
objective of this trial we aim to characterize pre- and post-treatment bladder tumor FGFR pathway 
phosphorylation changes, 6-month CR rates, and 1-year RFS rates according to FGFR3 over-expression versus 
mutation status. 
Biomarkers predictive of clinical efficacy and toxicity are emerging for VEGF directed therapies.  In a recent 
randomized placebo-controlled phase III study (ECOG 2100) of paclitaxel plus bevacizumab (a recombinant 
humanized monoclonal antibody to VEGF) in the first-line treatment of metastatic breast cancer, patients who 
received bevacizumab demonstrated a significant prolongation of progression free survival (11.8 vs. 5.9 
months, HR=0.60 p=0.001) (Miller et al., 2007).  When the entire study population was analyzed (n=772), no 
significant differences in median overall survival were observed between patients who received bevacizumab 
and those who received placebo (26.7 months vs. 25.2 months, HR 0.88 p=0.15).  In a planned biomarker 
analysis, the breast cancer tumor genotype frequencies of single nucleotide polymorphisms (SNPs) in seven 
VEGF and VEGF receptor genes were determined from patient formalin fixed paraffin embedded tissue blocks 
(FFPE).  Patients whose tumors possessed a VEGF (-2578 AA) or a VEGF (-1154 AA) genotype had a marked 
statistically significant improvement in median overall survival in association with bevacizumab therapy (-2578 
AA genotype HR 0.58 p=0.023, -1154 AA genotype HR 0.62 p=0.001) (Schneider et al., 2008).  Furthermore, 
significant associations between hypertension and patients with the VEGF (-634 CC) genotype (p=0.005) and 
the VEGF (-1498 TT) genotype (p=0.022) were also observed.  Confirmation of these observations is planned 
in a prospective large randomized phase III trial testing the role of bevacizumab in addition to standard 
chemotherapy for breast cancer patients in the adjuvant setting.  Lastly, investigators have also observed 
associations between the development of treatment related hypertension and favorable clinical outcomes in 
patients treated with VEGF directed therapies (Bono et al., 2011).  To date, no predictors of response to VEGF 
directed therapy have been examined or reported in bladder cancer.  Therefore as additional secondary 
objectives of this trial we plan to assess associations between improved biologic and clinical outcomes 
according to VEGFR over-expression, host VEGFR mutation, and treatment related hypertension status. 


 
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In addition, the ability to detect circulating tumor cells (CTCs) within the peripheral blood of cancer patients is 
well established (Yu et al., 2011).  While promising, the current FDA approved CellSearch® technology has 
significant limitations including, but not limited to: 1) the need for real time analysis of specimens within 72 
hours of collection; 2) the inability to do full genome profiling of CTC DNA/RNA; and 3) the dependence on 
tumor cells to express the pan-cytokeratin epithelial marker (EpCAM) on their cell surface and hence an 
inability to detect cells which have undergone epithelial to mesenchymal transformation (EMT).  Accordingly, 
investigators have begun examining more readily available means to identify, quantify, and characterize tumor 
genomic content circulating within patients.   The study of circulating free DNA/RNA (CFDNA/CFRNA) from 
peripheral blood and urine demonstrated feasibility in early studies (Gormally et al., 2007).  A particular 
advantage of CFDNA/CFRNA platforms is the ability to analyze banked frozen patients samples.  As a purely 
exploratory objective of this trial, we plan to assess the presence of FGFR3 mutations in patient baseline 
CFRNA from plasma and CFDNA from urine samples.  
Lastly, while dovitinib has demonstrated excellent systemic bioavailability in oral form and the bladder 
epithelium is well vascularized, confirmation of dovitinib reaching its target will greatly enhance the clinical 
interpretation of patient outcomes at the completion of the study.  As such, a final exploratory objective of this 
trial will be to measure bladder tissue concentrations of dovitinib at the initial post-treatment biopsy. 
2 Study Purpose/Rationale 
Due to the significant morbidity and quality of life detriments associated with cystectomy, new treatment 
approaches are clearly needed for BCG-refractory UC patients.  Given dovitinib’s dual targeting of the VEGFR 
and FGFR pathways, the preclinical activity of dovitinib in UC cell lines, the convenience of a daily oral 
administration, and a tolerable side effect profile, a strong rationale exists to test the clinical efficacy of 
dovitinib in BCG-refractory UC.  This is particularly true for patients with tumors harboring FGFR3 mutations 
or with FGFR3 over-expression. 
3 Objectives and Endpoints 
3.1 Primary Objectives 
 To determine the 6-month complete response rate in BCG-refractory UC patients with FGFR3 mutant 
or over-expressing tumors treated with dovitinib. 
3.1.1 Endpoint for Primary Objectives 
 The 6-month complete response rate is defined as the proportion of patients treated with dovitinib with 
no evidence of any remaining urothelial carcinoma tumors of any T-stage (including Tis) present 
within the bladder as assessed by standard of care cystoscopic examination with TURBT and urine 
cytology performed at 6 months after initiation of study therapy.   
 
NOTE: Patients with residual non-invasive UC tumors with no component of carcinoma in situ (i.e. 
Ta, T1) at 3-month cystoscopy and TURBT are not considered relapses and will be permitted to 
continue on dovitinib therapy.  If the subsequent 6-month cystoscopy/TURBT, and urine cytology 
shows no evidence of any remaining urothelial carcinoma in such patients, they will be considered a 
complete response.  Patients with any component of carcinoma in-situ (CIS) at 3-month 
cystoscopy/TURBT will be considered relapses and will not continue on dovitinib therapy. Any non-
invasive UC tumors (i.e. Ta, T1, Tis) at the 6-month or any subsequent cystoscopy/TURBT is 


 
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considered relapsed disease.  Similarly progression to invasive UC tumors (T2-T4) at any time point is 
also considered relapsed disease and patients will not continue on dovitinib therapy. 
 
3.2 Secondary Objectives 
 To determine the 1-year relapse free survival rate in BCG-refractory UC patients treated with 
dovitinib. 
 To determine the rate of progression to muscle-invasive stage (i.e. T2-T4). 
 To determine 3- and 6-month partial response rate defined as a reduction in T-stage on post-therapy 
TURBT (i.e. T1 -> Ta; T1+Tis -> Tis). 
 To characterize treatment related toxicity rates assessed by CTCAE v4.0. 
3.2.1 Endpoint for Secondary Objectives 
 The 1-year relapse free survival rate is defined as the proportion of patients treated with dovitinib with 
no evidence of any remaining urothelial carcinoma tumors at 12 months of follow-up.   
NOTE: Patients with residual non-invasive UC tumors with no component of carcinoma in situ (i.e. 
Ta, T1) at 3-month cystoscopy and TURBT are not considered relapses and will be permitted to 
continue on dovitinib therapy.  If the subsequent 6-month cystoscopy/TURBT, and urine cytology 
shows no evidence of any remaining urothelial carcinoma in such patients, they will be considered a 
complete response.  Patients with any component of carcinoma in-situ (CIS) at 3-month 
cystoscopy/TURBT will be considered relapses and will not continue on dovitinib therapy. Any non-
invasive UC tumors (i.e. Ta, T1, Tis) at the 6-month or any subsequent cystoscopy/TURBT is 
considered relapsed disease.  Similarly progression to invasive UC tumors (T2-T4) at any time point is 
also considered relapsed disease and patients will not continue on dovitinib therapy. 
 The rate of progression to muscle-invasive stage for dovitinib is defined as the proportion of patients 
with clinical or pathologic progression to muscle-invasive stages (i.e. T2-T4) at any time point on 
study. Pathologic progression is assessed by histological finding at TURBT or cystectomy.  Clinical 
progression is assessed by clinician’s physical exam and findings on radiologic imaging as ordered per 
the treating physician’s discretion. 
 The 3- and 6-month partial response rates are defined as the proportion of patients treated with 
persistent but reduced T-stage tumors on post-therapy TURBT (i.e. T1 -> Ta; T1+Tis -> T1). 
 Treatment related toxicity rates will be assessed by CTCAE v4.0. 
3.3 Exploratory Objectives 
 To characterize concordance rates between UC patient detected tumor, urine, and circulating free 
plasma FGFR3 mutations. 
 To characterize associations between pre-treatment germline (as assessed by PBMC extracted DNA) 
FGFR SNPs and post-treatment 6-month complete response rate and 1-year relapse free survival rate 
in patients treated with dovitinib. 
 To characterize associations between pre-treatment germline (as assessed by PBMC extracted DNA) 
VEGFR SNPs and post-treatment 6-month complete response rate and 1-year relapse free survival 
rate in patients treated with dovitinib. 


 
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 To characterize VEGFR over-expression status within tumor tissue 
 To characterize pre- and post-treatment bladder tumor FGFR and VEGFR pathway phosphorylation 
changes as assessed by bladder tumor tissue immunohistochemistry. 
 To characterize post-treatment bladder tissue dovitinib concentrations. 
 To characterize associations between post-treatment hypertension, 6-month complete response rate 
and 1-year relapse free survival rate in patients treated with dovitinib. 
3.3.1 Endpoint for Exploratory Objectives 
 Presence of FGFR3 mutations  (see Table 1-2) in tumor tissue and urine will be assessed by 
massively parallel sequencing of exons 7, 10, and 15 utilizing the Ion Torrent PGM instrument. 
Presence of FGFR3 mutations within patient free plasma will be assessed by PCR-amplification of 
the target regions and sequencing. 
 Pre-treatment germline FGFR SNPs will be assessed by testing extracted DNA from patient 
PBMC’s (collected prior to initiating dovitinib therapy) with validated commercial probes. 
 Pre-treatment germline VEGFR SNPs will be assessed by testing extracted DNA from patient 
PBMC’s (collected prior to initiating dovitinib therapy) with validated commercial probes. 
 Presence of VEGFR over-expression within tumor tissue will be assessed and interpreted by 
standard immunohistochemistry analysis with appropriate controls. 
 Pre- and post-treatment bladder tumor FGFR and VEGFR pathway phosphorylation changes will be 
assessed by bladder tumor tissue immunohistochemistry utilizing commercially available antibodies 
including, but not limited to, the following:  FGFR3, pFGFR3, VEGFR2, pVEGFR2, FRS2, pFRS2, 
ERK, pERK.   
 Post-treatment bladder tissue dovitinib concentrations will be assessed by TURBT fresh frozen 
tissue obtained at the 3-month cystoscopy  
 Hypertension will be defined as a systolic blood pressure (SBP) of ≥ 140 mmHg or a diastolic blood 
pressure (DBP) of > 90 mm Hg recorded at any time after dovitinib therapy is initiated. 
 
 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 Objectives and related endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
 To determine the 6-month 
complete response rate in 
BCG-refractory UC patients 
with FGFR3 mutant or 
overexpressing tumors 
treated with dovitinib 
 6-month complete response 
rate 
Refer to Section 10.5 
Key 
secondary 
 To determine the 1-year 
relapse free survival rate 
defined in BCG-refractory 
UC patients treated with 
dovitinib 
 To determine the rate of 
 1-year relapse free survival 
rate 
 
 
 
Refer to Section 10.6 


 
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Objective 
Endpoint 
Analysis 
progression to muscle-
invasive stage (i.e. T2-T4) 
 To determine 3- and 6-month 
partial response rate defined 
as a reduction in T-stage on 
post-therapy TURBT (i.e. T1 
-> Ta; T1+Tis -> Tis) 
 To characterize treatment 
related toxicity rates 
assessed by CTCAE v4.0 
 
 Muscle-invasive progression 
rate 
 
 3- and 6-month partial 
response rate 
 
 
 
 Treatment related toxicity rates 
Exploratory  To characterize pre- and 
post-treatment bladder 
tumor FGFR pathway 
phosphorylation changes  
 
 
 
 
 
 
 To characterize associations 
between pre-treatment 
germline (as assessed by 
PBMC extracted DNA) 
FGFR SNPs and post-
treatment 6-month complete 
response rate and 1-year 
relapse free survival rate in 
patients treated with 
dovitinib 
 
 To characterize pre- and 
post-treatment VEGFR 
pathway phosphorylation 
changes as assessed by 
bladder tumor tissue 
immunohistochemistry 
 
 
 
 
 
 
 To characterize associations 
between pre-treatment 
germline (as assessed by 
PBMC extracted DNA) 
VEGFR SNPs and post-
treatment 6-month complete 
response rate and 1-year 
relapse free survival rate in 
patients treated with 
dovitinib 
 
 To characterize associations 
between post-treatment 
hypertension 6-month 
 Pre- and post-treatment 
bladder tumor FGFR pathway 
phosphorylation changes will 
be assessed by bladder tumor 
tissue immunohistochemistry 
utilizing commercially 
available antibodies including, 
but not limited to, the 
following: FGFR3, pFGFR3, 
VEGFR2, pVEGFR2, FRS2, 
pFRS2, ERK, pERK 
 Pre-treatment germline FGFR 
SNPs will be assessed by 
testing extracted DNA from 
patient PBMC’s (collected 
prior to initiating dovitinib 
therapy) with validated 
commercial probes 
 
 
 
 
 Pre- and post-treatment 
bladder tumor VEGFR 
pathway phosphorylation 
changes will be assessed by 
bladder tumor tissue 
immunohistochemistry utilizing 
commercially available 
antibodies including, but not 
limited to, the following:  
FGFR3, pFGFR3, VEGFR2, 
pVEGFR2, FRS2, pFRS2, 
ERK, pERK 
 
 Pre-treatment germline VEGFR 
SNPs will be assessed by 
testing extracted DNA from 
patient PBMC’s (collected 
prior to initiating dovitinib 
therapy) with validated 
commercial probes 
 
 
 
 
 Hypertension will be defined as 
a systolic blood pressure 
(SBP) of > 140 mmHg or a 
Refer to Section 10.7 


 
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Objective 
Endpoint 
Analysis 
complete response rate and 
1-year relapse free survival 
rate in patients treated with 
dovitinib  
 
 To characterize concordance 
rates between UC patient 
detected tumor, urine and 
circulating free plasma 
FGFR3 mutations 
 
 
 
 
 
 
 To characterize post-
treatment bladder tissue 
dovitinib concentrations  
 
 
 
 To characterize VEGFR 
over-expression status 
within tumor tissue 
diastolic blood pressure (DBP) 
of > 90 mm Hg recorded at 
any time after dovitinib therapy 
is initiated 
 
Presence of FGFR3 mutation 
within patient tumor tissue, 
urine, will be assessed by 
massive parallel sequencing 
analysis of exons 7, 10, and 
15 utilizing Ion Torrent PGM 
instrument. Presence of 
FGFR3 mutation within patient 
free plasma will be assessed 
by PCR-amplification of the 
target regions and 
sequencing 
 Post-treatment bladder tissue 
obtained at 3-month TURBT 
will be analyzed by IUSCC 
Clinical Pharmacology 
Analytical core according to 
standard commercial assays 
 
 Presence of VEGFR over-
expression within tumor tissue 
will be assessed by standard 
IHC analysis 
 


 
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4 Investigational Plan 
4.1 Study Design 
This trial will be a single-arm, non-randomized, multi-center, phase II study conducted through 
Hoosier Cancer Research Network assessing the 6-month complete response rate and toxicity 
profile of oral dovitinib therapy in BCG-refractory urothelial carcinoma patients with tumors with 
FGFR3 mutations or over-expression who are ineligible for or refusing cystectomy.  A sample 
size of 20 evaluable patients receiving dovitinib therapy is expected (up to 50 patients screened).  
Study design is shown in Figure 4-1.  This study will characterize the clinical relevance and 
viability of FGFR3 and VEGFR as therapeutic targets in this biologically enriched population.  
Furthermore, due to the routine acquisition of pre- and post-treatment bladder biopsies as 
standard of care practice, this trial will significantly enhance identification and development of 
prognostic and predictive dovitinib biomarkers. 
Figure 4-1 
Study design 
 
4.1.1 Investigational Treatment, Other Study Treatment, Study Treatment, 
Supportive Treatment 
Investigational treatment in all patients will consist of oral dovitinib 500 mg taken once daily for 
5 consecutive days followed by 2 days off repeated every week.  Each treatment cycle will be 
defined as 28 days (4 weeks).  In patients not experiencing significant toxicity or relapsed 
disease, a study-defined  maximum  number of dovitinib cycles will not be stipulated.  Dovitinib 
will be supplied in the form of 100 mg hard gelatin capsules or film coated tablets.  
Standard of care cystoscopy and urine cytology will be performed every 3 months ± 7 days 
during the first 12 months of follow-up and per the treating urologist’s discretion thereafter.  
Standard of care tumor biopsy and bladder biopsies will be performed every 3 months ± 7 days 
during the first 6 months of follow-up and per the treating urologist’s discretion thereafter. 
Anti-emetic medications are permitted at the discretion of the treating physician. 
Colony stimulating growth factor (i.e. erythropoietin, darbopoeitin, pegfilgrastim, etc.) support is 
permitted at the discretion of the treating physician. 


 
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 Table 4-1 Study drugs  
Study drugs 
 
Investigational drug 
Dovitinib 
Standard of Care 
Cystoscopy with tumor biopsy, bladder biopsy, urine cytology 
Physician discretion 
Anti-emetic medications 
Physician discretion 
Colony stimulating growth factors 
4.1.2 Treatment Arms 
This trial is a single-arm non-randomized trial.  As such, all patients enrolled will receive 
dovitinib as outlined in section 4.1.1. 
4.2 Definition of End of the Study 
The study will end when all patients have either: 1) Confirmed relapsed disease OR 2) 12-months 
of follow-up after discontinuing dovitinib in the absence of relapsed disease. 
For early stopping rules for the study see section 10.10 Early Stopping Rules. 
4.3 Early Study Termination 
The study can be terminated at any time for any reason by the Sponsor Investigator or Novartis, 
the investigational drug supplier. Should this be necessary, the patient should be seen as soon as 
possible and treated as described in Section 7 for a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
5 Population 
The investigator or his/her designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered enrollment in the study. 
5.1 Inclusion Criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Histologically confirmed non-muscle invasive urothelial carcinoma of the bladder defined 
as Ta, T1, or Tis stage.  Tumor staging must be confirmed by TURBT performed within 42 
days prior to registration. 
2. Presence of either an FGFR3 mutation or FGFR3 over-expression within bladder tumor 
tissue. Somatic FGFR3 mutations (see Table 1-2) in exons 7, 10, and 15 will be assessed in 
FFPE tumor tissues by massively parallel sequencing analysis utilizing the Ion Torrent 
Personal Genome Machine (PGM) and performed in the CLIA-certified Molecular 
Pathology and Translational Research Laboratory at the Dartmouth Hitchcock Medical 
Center. FGFR3 over-expression will be assessed by standard IHC analysis performed 
within the Indiana University Simon Cancer Center Immunohistochemistry (IHC) Core 
Lab.   
NOTE:  Patients will initially be allowed to enroll if their tumors demonstrate either an 
FGFR3 mutation or FGFR3 over-expression.  However, a minimum of 10 FGFR3 


 
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mutation positive patients will be enrolled at study completion.  If 10 patients with tumors 
that are FGFR3 over-expressors but FGFR3 mutation negative are accrued prior to 
enrolling 10 FGFR3 mutation positive patients, subsequent enrollment will be restricted to 
patients with tumors that are FGFR3 mutation positive. 
3. Documented BCG-refractory disease defined as failure to achieve a tumor free state after 
at least 2 prior intravesical treatment courses, one of which must have been intravesical BCG 
therapy.   
NOTE: There is no maximum limit on the number of prior BCG therapy courses.  In 
addition, there is no maximum limit on the number of prior non-BCG intravesical therapy 
courses (i.e. gemcitabine, valrubicin, interferon, mitomycin C, etc.). 
4. Medically unfit to undergo cystectomy or electively choosing to forego cystectomy  
5. ECOG (WHO) performance status 0 or 1 or 2 
6. Age ≥ 18 years old 
7. Patients must have the following laboratory values: 
 White blood cell count (WBC) > 3.0 K/mm
3 
 Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
 Platelets ≥ 100 K/mm3 
 Hemoglobin (Hgb) ≥ 9 g/dL 
 Serum total bilirubin: ≤ 1.5 x ULN 
 ALT and AST ≤ 3.0 x ULN 
 Serum creatinine ≤ 1.5 x ULN or serum creatinine >1.5 – 3 x ULN if calculated 
creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockcroft-Gault equation, see 
formula below: 
CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is 
female multiply the above by 0.85) 
 Urine dipstick reading: Negative for proteinuria or, if documentation of +1 (+2 for 
patients with renal cell carcinoma) results for protein on dipstick reading, then 
total urinary protein ≤ 500 mg and measured creatinine clearance ≥ 50 
mL/min/1.73m2 from a 24 hour urine collection  
 
8. Patients who give a written informed consent obtained according to local guidelines 
5.2 Exclusion Criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients with muscle-invasive (i.e. T2, T3, T4), locally advanced non-resectable, or 
metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained 
within 28 days prior to study registration.  The required radiographic imaging includes: 
a. Abdomen/Pelvis – CT scan 
b. Chest – chest x-ray or CT scan 
2. Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive 
urothelial carcinoma.   


 
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3. Patients with another primary malignancy within 3 years prior to starting study drug, with 
the exception of adequately treated in-situ carcinoma of the uterine cervix, clinically 
localized prostate cancer, biochemically relapsed non-metastatic prostate cancer (i.e. PSA 
only disease), or skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or 
non-melanomatous skin cancer) 
4. Patients who have received the last administration of an anticancer therapy including 
chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting 
study drug, or who have not recovered from the side effects of such therapy 
5. Patients who have received targeted prior VEGFR or FGFR-targeted agents (i.e. sunitinib, 
pazopanib, sorafenib, bevacizumab, axitinib, etc.).  
6. Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have 
not recovered from radiotherapy toxicities 
7. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-
pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, 
or patients who have had minor procedures (i.e. TURBT), percutaneous biopsies or 
placement of vascular access device ≤ 1 week prior to starting study drug,  or who have 
not recovered from side effects of such procedure or injury 
8. Patients with any of the following concurrent severe and/or uncontrolled medical 
conditions which could compromise participation in the study: 
 Impaired cardiac function or clinically significant cardiac diseases, including any of 
the following: 
a. History or presence of serious uncontrolled ventricular arrhythmias 
b. Clinically significant resting bradycardia 
c. LVEF assessed by 2-D echocardiogram (ECHO) <  50% or lower limit of 
normal (whichever is higher) or multiple gated acquisition scan (MUGA), 
< 45% or lower limit of normal (whichever is higher) 
d. Any of the following within 6 months prior to starting study drug: 
myocardial infarction (MI), severe/unstable angina, Coronary Artery 
Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular 
Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism 
(PE) 
e. Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 
100 mm Hg, with or without anti-hypertensive medication(s) 
 Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 
 Cirrhosis, chronic active hepatitis or chronic persistent hepatitis 
 Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is 
not mandatory)   
 Patients who are currently receiving anticoagulation treatment with therapeutic 
doses of warfarin.  Full-dose anti-coagulation with low molecular weight heparin is 
permitted. 
 Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. 
active or uncontrolled infection, uncontrolled diabetes) that could cause 
unacceptable safety risks or compromise compliance with the protocol 


 
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9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception (defined 
below). Highly effective contraception must be used by both sexes (female patients and their 
male partners) during study treatment and for 30 days after the last dose of study 
medication.  
 Highly effective contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
 Combination of the following (a+b): 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b.Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository  
Oral, implantable, or injectable hormone contraceptives may be affected by cytochrome P450 
interactions, and are therefore not considered effective for this study 
Women of child-bearing potential (sexually mature women) who have not undergone a 
hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive 
months (i.e., who has had menses any time in the preceding 12 consecutive months), must 
have a negative serum pregnancy test ≤ 14 days prior to starting study drug. 
11. Fertile males not willing to use contraception. Fertile males must use condom with 
spermicide. Highly effective contraception, as defined above, must be used by both sexes 
(male patients and their female partners) during study treatment and for 90 days after the last 
dose of study medication and should not father a child in this period. A condom is required to 
be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.   
12.  Patients unwilling or unable to comply with the protocol 
6 Treatment 
6.1 Treating the Patient 
The investigator needs to instruct the patient to take the study drug dovitinib as per protocol.  All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on a drug accountability form (see study procedure manual [SPM] for example) and 
entered into the EDC system. 
6.1.1 Administration  
Dovitinib will be dosed on a flat scale of 500 mg (i.e. 5 x 100 mg per capsule/tablet) on a 5 days 
on/2 days off dosing schedule. Dovitinib may be taken with or without food.  
 


 
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 If a patient forgets to take dovitinib at the routinely scheduled time, then the patient can take 
dovitinib within 6 hours of the routinely scheduled time.  If a dose is not taken within this 6 
hour window, it should be skipped. If a patient’s dose is skipped on a given day, then the 
patient should resume dovitinib at the routinely scheduled time the next morning, provided it 
is a scheduled day of dosing. 
 If a patient routinely takes his/her dose of dovitinib in the evening, and forgets to take 
dovitinib as scheduled, then the patient can take dovitinib within 6 hours of the routinely 
scheduled time.  If a dose is not taken within this 6 hour window, it should be skipped. The 
patient should resume dovitinib at the routinely scheduled time the next evening, provided it 
is a scheduled day of dosing. 
 
 


 
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6.1.2 Dosing and Treatment Schedule  
Table 6-1 Dosing and treatment schedule 
Study drugs 
Pharmaceutical form 
and route of 
administration 
Dose 
Frequency 
Dovitinib 
Capsule/tablet for oral 
use 
500 mg  
5 days on/2 days off 
6.1.3 Dose Modification and Dose Delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study drug. The following guidelines need 
to be applied: 
 
These changes must be recorded in the eCRF. 
 
Table 6-2 Dose reduction steps for dovitinib  
Dose reduction* 
 
Starting dose level - 0 
Dose level - 1 
Dose level - 2 
Dovitinib 
500 mg 
400 mg 
300 mg** 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
**Dose reduction below 300 mg is not allowed. 
 
6.1.4 Treatment Interruption and Treatment Discontinuation 
 
Toxicity intensity a 
Dose modification b, c 
Cardiovascular 
Hypertension 
Treatment-emergent hypertension should be treated as per 
standard cardiology practice.  Recommended agents for the 
management of blood pressure elevations on dovitinib include 
angiotensin-converting enzyme inhibitors and calcium channel 
blockers. 
SBP < 160 mmHg and/or DBP < 100 mm 
Hg, with or without anti-hypertensive 
medication  
Maintain dose level 
 
SBP ≥160 mmHg and/or DBP ≥ 100 mm 
Hg, with or without anti-hypertensive 
medication, but not immediately life-
threatening 
Delay the study treatment and initiate/intensify antihypertensive 
therapy.  
Dovitinib may be restarted in conjunction with standard anti-
hypertensive medication if BP is controlled (i.e. BP < 160/100 
mmHg).  
Once BP is controlled after suspending dovitinib, maintain dose 
level or ↓ 1 dose level at the discretion of the investigator. 
Life-threatening consequences  
(e.g., malignant hypertension,  
transient or permanent  
neurologic deficit, hypertensive  
crisis); urgent intervention  
Discontinue study treatment permanently 
 


 
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Toxicity intensity a 
Dose modification b, c 
indicated  
Left ventricular systolic dysfunction 
 
Left ventricular ejection fraction (LVEF) ≥ 
50%/LLN (ECHO), or ≥ 45%/LLN 
(MUGA) 
Maintain dose level 
LVEF < 50%/LLN (ECHO), or < 
45%/LLN (MUGA), or 
Symptomatic due to drop in ejection 
fraction responsive to intervention 
Delay study treatment until resolved to ≥ 50%/LLN (ECHO) or 
≥45%/LLN (MUGA), then ↓ 1 dose level 
Refractory or poorly controlled heart 
failure due to drop in ejection fraction; 
intervention such as ventricular assist 
device, intravenous vasopressor support 
or heart transplant indicated 
Discontinue study treatment 
Other cardiovascular 
 
Grade 1 
Maintain dose level 
Grade 2 
Maintain dose level 
If asymptomatic decrease of LVEF by absolute value of 20% and 
to <LLN, delay study treatment until resolved to ≤ grade 1, then ↓ 1 
dose level 
Grade 3 
Delay study treatment until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Grade 4 
Discontinue study treatment 
Gastrointestinal 
Diarrhea 
At the first sign of abdominal cramping, loose stools, or onset of 
diarrhea, it is recommended that the patient be treated according 
to institutional standard of care  
Grade 1 (despite maximal anti-diarrheal 
medication) 
Maintain dose level 
Grade 2 (despite maximal anti-diarrheal 
medication) 
 
Delay study treatment, until resolved to ≤ grade 1, then re-start at 
the current dose level 
If diarrhea returns as ≥ grade 2, then suspend dose until resolved 
to ≤ grade 1, then ↓ 1 dose level 
Grade  3/4  (despite  maximal  anti-
diarrheal medication) 
Delay study treatment until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Nausea 
Suspend dose for CTCAE grade 2-3 nausea only if it could not be 
controlled despite the use of standard anti-emetics. 
Grade 1 (despite standard anti-emetics) 
Maintain dose level 
Grade 2 (despite standard anti-emetics) 
Delay study treatment, until resolved to ≤ grade 1, and then re-
start at the current dose level. 
If nausea returns as ≥ grade 2, then suspend dose until resolved to 
≤ grade 1, then ↓ 1 dose level. 
Grade 3 (despite standard anti-emetics) 
Delay study treatment until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Vomiting 
Suspend dose for CTCAE grade 2-4 vomiting only if it could not be 
controlled despite the use of standard anti-emetics. 
Grade 1 (despite standard anti-emetics) 
Maintain dose level 
Grade 2 (despite standard anti-emetics) 
Delay study treatment, until resolved to ≤ grade 1, and then re-
start at the current dose level. 
If nausea returns as ≥ grade 2, then suspend dose until resolved to 
≤ grade 1, then ↓ 1 dose level. 
Grade 3/4 (despite standard anti-
emetics) 
Delay study treatment until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Hematologic 


 
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Toxicity intensity a 
Dose modification b, c 
Febrile neutropenia (Grade 3 or 4) 
(Per protocol) fever of unknown origin 
without clinically or microbiologically 
documented infection (ANC <1.0 x 109/L, 
fever ≥ 38.5°C)  
Delay study treatment until resolved, then ↓ 1 dose level 
≥ Grade 3 anemia judged to be a 
hemolytic process secondary to study 
treatment  
Discontinue study treatment. 
≥ Grade 3 lymphopenia considered 
clinically significant  
Requires dose interruption until resolved to ≤ grade 1, then ↓ dose 
level. 
Neutropenia/Neutrophil count decreased  
Grade 1 or 2 
Maintain dose level 
Grade 3 
Grade 4 
Delay study treatment until resolved to ≤ grade 2, then: 
If resolved by ≤ 7 days after suspending dovitinib, maintain dose 
level 
If resolved by > 7 days after suspending dovitinib, ↓ 1 dose level 
Thrombocytopenia/Platelet count 
decreased 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay study treatment until resolved to ≤ grade 1, then: 
If resolved by ≤ 7 days after suspending dovitinib, maintain dose 
level 
If resolved by > 7 days after suspending dovitinib, ↓ 1 dose level 
Grade 4 
Delay study treatment until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Hepatic 
≥ grade 3 alkaline phosphatase or GGT 
Isolated values of ≥ grade 3 alkaline phosphatase or GGT values 
will NOT require dose interruption. 
ALT or AST 
 
≤ 3.0 x ULN   
Maintain dose level with LFTse monitored as per protocol. 
> 3.0 to ≤ 5.0 x ULN,  
without bilirubin elevation to > 2.0 x ULN 
Maintain dose level with weekly monitoring of LFTse, or more 
frequently if clinically indicated, until resolved to ≤ grade 1 or 
baseline. 
> 5.0 x ULN 
Delay study treatment until resolved to ≤ grade 1 or baseline, then 
↓ 1 dose level.  
Monitor LFTse weekly, or more frequently if clinically indicated, for 
8 weeks; then, every 2 weeks for 4 weeks; then, every 4 weeks as 
per protocol. 
Following re-introduction of dovitinib, if ALT or AST elevations > 3 
x ULN recur as assessed on 2 separate measurements no more 
than 1 week apart, then study treatment should be permanently 
discontinued.  
If study treatment is permanently discontinued, then patients 
should be monitored weekly (including LFTse), or more frequently if 
clinically indicated, until AST or ALT have resolved to ≤ grade 1 or 
stabilization (i.e., no CTCAE grade change over 4 weeks). 
 
 
Total bilirubin 
 
≤ 1.5 x ULN  
Maintain dose level with LFTse monitored as per protocol. 
> 1.5 to 3.0 x ULN 
with ALT or AST ≤ 3.0 x ULN 
Maintain dose level with LFTse monitored as per protocol. 
 


 
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Toxicity intensity a 
Dose modification b, c 
> 3.0 x ULN 
Discontinue study treatment permanently. 
Patients should be monitored weekly (including LFTse), or more 
frequently if clinically indicated, until total bilirubin has resolved to ≤ 
grade 1 or stabilization (i.e., no CTCAE grade change over 4 
weeks). 
Note: If grade 3 or grade 4 hyperbilirubinemia is due to the indirect 
component only, and hemolysis as the etiology has been ruled out 
as per institutional guidelines (e.g., review of peripheral blood 
smear and haptoglobin determination), then ↓ 1 dose level and 
continue treatment at the discretion of the investigator. 
ALT or AST, and concurrent Bilirubin 
elevation 
 
ALT or AST > 3.0 x ULN  
AND 
Total Bilirubin > 2.0 x ULN 
Discontinue study treatment permanently. 
Patients should be monitored weekly (including LFTse), or more 
frequently if clinically indicated, until ALT/AST and total bilirubin 
have resolved to ≤ grade 1 or stabilization (i.e., no CTCAE grade 
change over 4 weeks). 
Renal 
Serum creatinine 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay study treatment until resolved to ≤ grade 1 or baseline, then 
↓ 1 dose level 
Grade 4 
Discontinue study treatment 
Amylase and/or lipase elevations 
 
Asymptomatic Grade 1 or 2 
Maintain dose level 
Asymptomatic Grade 3 or 4 
Patients who develop grade 3 or 4 hyperlipasemia or 
hyperamylasemia without clinical or other evidence of pancreatitis 
may continue study medication without interruption 
Pancreatitis 
Grade 2 
Maintain dose level 
Grade 3 or 4 
Discontinue study treatment 
Hand-foot syndrome 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay study treatment until resolved to ≤ grade 1 then ↓ 1 dose 
level 
Grade 4 
Discontinue study treatment 
Other clinically significant adverse events 
Grade 1 or 2 
Maintain dose level 
Grade 3 (except hyperlipidemia d) 
Delay study treatment until resolved to ≤ grade 1 or baseline,  
then maintain dose level or ↓ 1 dose level at the discretion of the 
investigator 
Grade 4 
Delay study treatment until resolved to ≤ grade 1 or baseline,  
then ↓ 1 dose level or discontinue dovitinib at the discretion of the 
investigator 
All dose modifications should be based on the worst preceding toxicity. 
a Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
b Patients are allowed two dose reductions: a dose reduction to 400 mg from 500 mg, and, if necessary, a dose 
reduction to 300 mg from 400 mg. 
c If a patient requires a dose interruption of > 14 days starting from the first day a dose was missed, then the 
patient must be discontinued from the study.  Patients who discontinue the study for a study related adverse 


 
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Toxicity intensity a 
Dose modification b, c 
event including an abnormal laboratory value must be followed at least once a week for 4 weeks and 
subsequently at 4 week intervals until resolution or stabilization of the event, whichever comes first. 
d Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed using 
standard therapies. Fluvastatin and Rosuvastatin may have potential of drug to drug interactions. If these 
statins are prescribed, close clinical monitoring including serum lipids is required since dovitinib could reduce 
the exposure of statins. Statins should be prescribed according to product label/data sheets for HMG-CoA 
reductase inhibitors. Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 or higher 
hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or Grade 2 or higher hypertriglyceridemia (>2.5 x ULN) 
should be treated with fibrate, or appropriate lipid-lowering medication in addition to diet. 
 
e LFTs include albumin, ALT, AST, total bilirubin (fractionated [direct and indirect], if total bilirubin > 
2.0 x ULN), alkaline phosphatase (fractionated [quantification of isoenzymes], if alkaline 
phosphatase ≥ Grade 2), and GGT. 
 
 
6.1.5 Permitted Concomitant Therapy 
Anti-emetic medications are permitted at the treating physician’s discretion. 
Colony stimulating growth factor (i.e. erythropoietin, darbopoietin, pegfilgrastim) support is 
permitted at the treating physician discretion. 
Full dose anti-coagulation with low molecular weight heparin (i.e. enoxaparin, fondaparinux) is 
permitted.   
The patient needs to notify the investigational site about any new medications he/she takes after 
the start of the study drug. All medications (other than study drug) and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient starts 
treatment with study drug must be recorded in the eCRF. 
6.1.6 Prohibited Concomitant Therapy 
Full dose anti-coagulation with warfarin is not permitted. 
6.1.7 Hormonal Contraception Excluded 
Hormonal contraception is not allowed during the study.  Women of childbearing potential are 
required to use two forms of highly effective contraceptives (e.g. male condom with spermicidal; 
diaphragm with spermicide; intra-uterine device). 
6.2 Study Drug(s) 
6.2.1 Packaging and Labeling 
Dovitinib will be provided as a gelatin capsule or film coated tablet of 100 mg strength  . The 
capsules/tablets will be provided in either blisters or bottles. Dovitinib medication labels will 
comply with the legal requirements of each country and be printed in the local language.  The 
inactive ingredients for the dovitinib capsules are pregelatinized starch, colloidal silicon dioxide, 
microcrystalline cellulose, and magnesium stearate.  
6.2.2 Supply, Receipt and Storage 
The study drug must be stored in a secure area, limited access area. The storage conditions are 


 
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described on the medication label. It will be administered only to patients entered into the clinical 
study, at no cost to the patient, in accordance with the conditions specified in this protocol.  The 
capsules/tablets should be stored according to the label in a secured, limited access area until 
required.  
 
Investigational pharmacy will maintain accurate records demonstrating dates and amount of study 
drug shipped, to whom dispensed (patient by patient accounting), and accounts of any study 
treatment accidentally or deliberately destroyed.  At the end of the study, reconciliation must be 
made between the amount of study drug supplied, dispensed, and subsequently destroyed or 
returned.  
Details are listed in Table 6-3 below. 
 
Table 6-3 Drug Supply and Storage 
6.2.3 Dispensing and Preparation 
Capsules/tablets including instructions for administration are dispensed by study personnel on an 
outpatient basis. 
Patients will be provided with adequate supply of study drug for self-administration at home 
until at least their next scheduled study visit. 
6.2.4 Drug Compliance and Accountability 
6.2.4.1 Drug Compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the drug accountability 
form (see SPM).  This information must be captured in the source document at each patient visit. 
6.2.4.2 Drug Accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing of 
study drug in a drug accountability form (see SPM). Drug accountability will be documented. 
Patients will be asked to return all unused study drug and packaging on a regular basis, at the end 
of the study or at the time of study drug discontinuation. 
6.2.5 Disposal and Destruction  
Any unused study dovitinib will be documented and disposed of according to institutional 
standards. Documentation of the destruction should be recorded on the drug accountability form 
(see SPM). 
6.2.6 Other Concomitant medication 
Patients must be instructed not to take additional medications including over-the-counter products 
and herbal/alternative medications during the study without prior consultation with the 
Study drugs 
Supply 
Storage 
Dovitinib 
Centrally supplied by Novartis 
Please see study drug label 


 
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investigator. It is important to avoid concomitant medications that are known to cause 
hepatotoxicity. 
Oral contraceptives are generally metabolized by CYP3A4/2C9, and act also as a moderate 
inhibitor of CYP1A2, therefore should not be used. Thus, patients who are sexually active and are 
using oral contraceptives as a method of contraception should change to two highly effective 
contraceptive methods during the study participation. 
Permitted treatments during the study include, but are not limited to the following: 
 Pain medication to allow the patient to be as comfortable as possible 
 Nutritional support or appetite stimulants (e.g. megestrol) 
 Oxygen therapy and blood products or transfusions 
 Prophylactic anti-emetics are allowed for patients who, at the discretion of the investigator, 
have experienced ≥ grade 1 nausea or vomiting. 
 Hematopoietic growth factors should be used according to the guidelines established by the 
American Society of Clinical Oncology (ASCO) or as dictated by local practice. The ASCO 
guidelines are available [http://jco.ascopubs.org/cgi/content/full/24/19/3187] 
 The administration of anticoagulation and antiaggregation agents (e.g. eptifibatide, 
epoprosterol, prasugrel, dipyridamole, fondaparinux) should be allowed except prasugrel, due 
to its potential drug-drug interaction with dovitinib.  Prasugrel is primarily metabolized by the 
CYP3A4 and CYP2B6 and to a lesser extent by the CYP2C9 and CYP2C19. In vitro study 
demonstrated that dovitinib is an inducer of CYP2C9 and CYP2C19, co-administration of 
dovitinib with prasugrel is likely to reduce the exposure of prasugrel. For oral anticoagulants, 
the upper limit of INR is < 1.5. 
 The administration of androgen deprivation therapy or orchiectomy as part of the definitive 
treatment for clinically localized prostate cancer or biochemically relapsed non-metastatic 
(i.e. PSA relapse only) is permitted. 
The following concomitant treatments are not allowed during the study: 
 Concurrent use of isoniazid, labetalol, trovafloxacin, tolcapone, and felbamate are not 
permitted, since alternative less hepatotoxic drugs are available to use. 
 Concurrent use of other investigational drugs is not permitted. 
 The administration of other antineoplastic therapy (e.g. chemotherapy, immunotherapy, 
targeted therapy, monoclonal antibodies and radiation therapy) is not permitted. 
 The administration of anti-androgen therapy (e.g. bicalutamide, flutamide, nilutamide) for the 
treatment of prostate cancer is not permitted. 
 The administration of androgen deprivation therapy or orchiectomy for the treatment of 
metastatic prostate cancer is not permitted. 
6.2.7  Pharmacokinetic Interactions  
Dovitinib is metabolized mainly by CYP1A1/2 and FMO. FMO is not readily induced or 
inhibited by any other agents, therefore the drug-drug interactions between dovitinib and FMO 
inducers/inhibitors are of lesser concern. To a lesser extent, dovitinib could be metabolized by 
CYP3A4, CYP2C8, and CYP2D6 enzymes. 
Though no drug interactions have been studied clinically, drugs that inhibit (ciprofloxacin, 
clinafloxacin, enoxacin, fluvoxamine, oltipraz, propranolol, rofecoxib, thiabendazole, and 
zafirlukast) or induce CYP1A1/2 (omeprazole and tobacco) may interact with dovitinib and 
should be used with caution. 


 
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In vitro, dovitinib has a potential to induce CYP1A2 activity 2- to 14-fold, as well as CYP2C9 
and CYP2C19 activity to a lesser extent (< 3- to 4-fold). Therefore, CYP1A2, CYP2C9, and 
CYP2C19 substrates as listed below should also be used with caution: 
 
• CYP1A2 substrates: clozapine, cyclobenzaprine, imipramine, mexiletine, naproxen, 
riluzole, tacrine, and theophylline. 
 
• CYP2C9 substrates: losartan, irbesartan, diclofenac, ibuprofen, piroxicam, tolbutamide, 
glipizide, celecoxib, fluvastatin, naproxen, phenytoin, rosiglitazone, sulfamethoxazole, 
tamoxifen, tolbutamide, torsemide, and warfarin. 
 
• CYP2C19 substrates: diazepam, phenytoin, phenobarbital, lansoprazole, omeprazole, 
pantoprazole, rabeprazole, amitriptyline, clomipramine, clopidogrel, cyclophosphamide 
and progesterone. 
7 Visit schedule and assessments 
7.1 Study Flow and Visit Schedule 
Table 7-1 lists all of the assessments except for laboratory assessments and indicates with an “X” 
the visits when they are performed.  Table 7-2 lists all laboratory assessments.  All data obtained 
from these assessments must be supported in the patient’s source documentation. The table 
indicates which data are entered into the database (D) or may remain in source documents only 
(S) (column category).  Assessments that generate data for the EDC system are listed.   
Since dovitinib is given in a 5 days on/2 days off dosing schedule, day 12 assessments are 
intended to be performed on the last dosing day of the 2nd week in cycle 1 and cycle 2 and day 26 
assessments are intended to be performed on the last dosing day of the 4th week in cycle 1 and 
cycle 2. 
All assessments have a ±3 days window unless otherwise indicated.  In the event of public 
holidays (e.g. Christmas, New Year’s Day), there is a ±5 days window on all assessments. Every 
effort must be made to follow the schedule of assessments within the windows outlined in the 
protocol.  Additional assessment may be performed as clinically indicated.  


 
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Table 7-1 Visit evaluation schedule  
 
Category 
Reference to 
assessment 
types 
Baseline 
Cycle 1 
Cycle 2 Subsequent 
cycles 
End of 
study 
treatment 
Visit no. 
 
 
1 
2 3 4 5 6 
7+ 
 
Day of cycle 
 
 
-28 to -1 1 12 26 12 26 
26 (or 28) 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Assessments 
 
 
 
 
 
 
 
 
 
 
 
Obtain Informed Consent 
D 
 
X 
 
 
 
 
 
 
 
Demography 
D 
7.10.1 
X 
 
 
 
 
 
 
 
Inclusion / exclusion 
criteria 
S 
5.1, 5.2 
X 
 
 
 
 
 
 
 
Relevant medical 
history/previous medical 
conditions 
D 
 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
D 
 
X 
Continuous 
Adverse events 
D 
 
X 
Continuous 
Registration  
D 
 
X 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
D 
7.10.2 
X 
 
 
 
 
 
 
 
Prior antineoplastic 
therapy 
D 
7.10.3 
X 
 
 
 
 
 
 
 
Vital signs 
D 
7.10.4 
X(<14) 
 X X X X 
X 
X 
Physical examination 
D 
 
X (<14) 
 
 
X 
 
X 
X 
X 
ECOG PS 
D 
7.10.5 
X (<14) 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
 
Dovitinib dosinga 
D 
 
 
X X X X X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Assessments 
 
 
 
 
 
 
 
 
 
 
 
FGFR3 mutation / 
overexpression status 
D 
7.10.6 
Xf 
 
 
 
 
 
 
 
Cystoscopy 
D 
7.10.7 
Xb 
 
 
 
 
 
Xb 
 
TURBT 
D 
7.10.7 
Xc 
 
 
 
 
 
Xc 
 
Urine cytology 
D 
7.10.7 
Xd 
 
 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
Radiographic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Abdomen/pelvis 
D 
7.10.8 
X 
 
 
 
 
 
 
 
Chest x-ray or CT 
D 
7.10.8 
X 
 
 
 
 
 
 
 
 
 


 
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Category 
Reference to 
assessment 
types 
Baseline 
Cycle 1 
Cycle 2 Subsequent 
cycles 
End of 
study 
treatment 
Visit no. 
 
 
1 
2 
3 
4 
5 
6 
7+ 
 
Day of cycle 
 
 
-28 to -1 1 12 26 12 26 
26 (or 28) 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Assessments 
 
 
 
 
 
 
 
 
 
 
 
2-D Echo or MUGA 
D 
7.10.9 
X 
 
 
 
 
 
Xe 
X 
ECG 
D 
7.10.9 
X 
 
X 
X 
 
 
Xe 
X 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies 
 
 
 
 
 
 
 
 
 
 
 
FGFR1  and  FGFR2 
mutation status 
S 
7.10.6 
 
Xg 
 
 
 
 
 
 
VEGFR1/2/3  mutation / 
overexpression status 
S 
7.10.6 
 
Xg 
 
 
 
 
 
 
Plasma  
FGFR3 
mutations 
S 
7.10.10 
 
Xg 
 
 
 
 
 
 
Urine FGFR3 mutations 
S 
7.10.10 
 
Xg 
 
 
 
 
 
 
Tumor dovitinib PK 
S 
7.10.10 
 
 
 
 
 
 
Xh 
 
FGFR  
&  
VEGFR 
Pathway Signaling on 
TURBT samples 
S 
7.10.6.6 
 
Xi 
 
 
 
 
Xi 
 
a. Dovitinib will be dosed on a flat scale of 500 mg (i.e. 5 x 100 mg per capsule/tablet) on a 5 days on/2 days 
off dosing schedule. See section 6.1.1 for further detail. 
b. Initial baseline cystoscopy must be performed within 42 days of study registration.  Subsequent cystoscopic 
evaluations will be performed every 3 months +/- 7 days (e.g. 3 month, 6 month, 9 month, 12 month) during 
the first year of follow-up and as clinically indicated per treating physician thereafter. Note: Patients with 
residual non-invasive UC tumors with no CIS at initial 3-month cystoscopy/TURBT are not considered 
relapses. Patients with any component of CIS at initial 3-month cystoscopy and TURBT will be considered 
relapses and will not continue on dovitinib therapy. Any non-invasive UC tumors (i.e. Ta, T1, Tis) at the 6-
month or any subsequent cystoscopy/TURBT is considered relapsed disease.  Similarly progression to 
invasive UC tumors (T2-T4) at any time point is also considered relapsed disease and patients will not 
continue on dovitinib therapy. See section 7.10.11.2 for details. 
c. Initial TURBT must be performed within 42 days of study registration.  Subsequent TURBT’s will be 
performed every 3 months +/- 7 days (e.g. 3 month, 6 month) during the first 6-months of follow-up and as 
clinically indicated per treating physician thereafter. Note: Patients with residual non-invasive UC tumors 
with no CIS at initial 3-month cystoscopy/TURBT are not considered relapses. Patients with any component 
of CIS at initial 3-month cystoscopy and TURBT will be considered relapses and will not continue on 
dovitinib therapy. Any non-invasive UC tumors (i.e. Ta, T1, Tis) at the 6-month or any subsequent 
cystoscopy/TURBT is considered relapsed disease.  Similarly progression to invasive UC tumors (T2-T4) at 
any time point is also considered relapsed disease and patients will not continue on dovitinib therapy. See 
section 7.10.11.2 for details. 
d. Initial urine cytology must be performed within 42 days of study registration.  Subsequent urine cytologies 
will be performed every 3 months +/- 7 days (e.g. 3 month, 6 month, 9 month, 12 month) during the first year 
of follow-up and as clinically indicated per treating physician thereafter 
e. Subsequent on-treatment Echo and ECG testing to be performed only as clinically indicated 
f. Mandatory submission of unstained slides from TURBT specimen must be submitted for FGFR3 
mutation/overexpression status prior to study registration. Refer to SPM for collection and shipping 


 
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guidelines. 
g. Archived pre-treatment tissue samples for study correlatives will be collected from enrolled eligible patients. 
Blood and urine samples for study correlatives will be collected at Cycle 1 Day 1 from enrolled eligible 
patients.  The correlative analyses will be completed in batch groupings at study completion. Refer to SPM 
for collection, processing and shipping guidelines. 
h. Tissue for dovitinib PK analysis will be collected at the initial post-treatment cystoscopy with TURBT 
performed 3 months +/- 7 days after starting dovitinib therapy. Refer to SPM for collection, processing and 
shipping guidelines. 
i. Unstained slides are to be submitted from the pre-treatment TURBT specimen and from the post-treatment 
cystoscopy with TURBT performed 3 months +/- 7 days after starting dovitinib therapy. Refer to SPM for 
collection and shipping guidelines. 
 
 


 
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Table 7-2 Laboratory assessment schedule  
 
Test name 
Category Reference to 
assessment 
types 
Baseline Cycle 1 
Cycle 2 Subsequent 
cycles 
End of study 
treatment 
Visit no. 
 
 
 
1 
2 3 
4 
5 
6 
7+ 
 
Day of cycle  
 
 
-14 to -1 1 12 26 12 26 26 
 
Hematology Hemoglobin 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
RBC 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
WBC 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Platelets 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Differentials:  
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
ANC 
D 
 
 
 
 
 
 
 
 
 
 
lymphocytes S 
 
 
 
 
 
 
 
 
 
 
monocyte S 
 
 
 
 
 
 
 
 
 
 
eosinophil S 
 
 
 
 
 
 
 
 
 
 
basophil S 
 
 
 
 
 
 
 
 
 
Chemistry 
Urea/BUN 
S 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Creatinine 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Total bilirubin D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
ALT 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
AST 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
GGT 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Alkaline 
phosphatase 
S 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Albumin 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Total protein S 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Calcium 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Sodium 
S 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Magnesium 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Potassium 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Phosphorous D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Glucose 
S 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
LDH 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Amylase 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
 
Lipase 
D 
7.10.11 
X 
X X 
X 
X X 
X 
X 
Serum lipid 
profile 
Total 
cholesterol, 
triglycerides, 
LDL, HDL 
S 
7.10.11 
X 
 
 
X 
 
X 
X 
X 
Coagulation PT or INR 
S 
7.10.11 
X 
 
 
 
 
X 
Xa 
 
 
PTT 
S 
7.10.11 
X 
 
 
 
 
X 
Xa 
 
 
Fibrinogen 
S 
7.10.11 
X 
 
 
 
 
X 
Xa 
 
 
 


 
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Urinalysis 
Dipstick: 
specific 
gravity, PH, 
protein, 
blood, 
glucose... 
S 
7.10.11 
Xf 
 
 
Xb  
Xb Xb 
 
 
Microscopic: 
WBC, RBC, 
bacteria, 
casts... 
S 
7.10.11 
X 
 
 
Xb  
Xb Xb 
 
Thyroid 
function 
TSH, T3, T4 D 
7.10.11 
X 
 
 
 
 
 
Xc 
X 
Cardiac 
enzymes 
CPK, CK-
MB, troponin 
T or I 
S 
7.10.11 
X 
 
 
Xd  
Xd Xd 
 
Pregnancye 
test 
 
S 
7.10.11 
X 
 
 
X 
 
X 
X 
 
aAdditional PT/INR, PTT, and Fibrinogen studies will be performed only as clinically indicated in 
subsequent treatment cycles. 
bAdditional urine dipstick and microscopic studies will be performed only as clinically indicated in 
subsequent treatment cycles. 
cAdditional TSH, T3, and T4 studies will be performed (+/- 5 days) on cycle 3 day 26, cycle 6 day 
26 and as clinically indicated in subsequent treatment cycles. 
dAdditional CPK, CK-MB, troponin T or I studies will be performed only as clinically indicated in 
subsequent treatment cycles. 
eA serum pregnancy test will be assessed in female patients of childbearing potential within 14 
days of registration and on day 26 (± 5 days) of all subsequent treatment cycles. 
fIf documentation of +1 (+2 for patients with renal cell carcinoma) results for protein on dipstick 
reading, a 24 hour urine for protein must be obtained 
 


 
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7.2 Biomarkers 
All patients will be required to have bladder tumor FGFR3 mutation and over-expression status 
determined from a TURBT sample obtained within 42 days of registration.  All other biomarker 
analyses will be exploratory in nature and do not need to be performed as part of study screening 
or eligibility assessments.   
7.3 Eligibility Screening and Patient Registration  
Patient eligibility will be confirmed through the Hoosier Cancer Research Network’s secure web-
based electronic data capture system.  Once eligibility criteria are entered and the patient is 
confirmed as eligible, the EDC system will assign a unique patient identification number to the 
patient, and register the patient.   
Patients must be registered prior to starting protocol therapy and begin therapy within 5 working 
days of registration. 
Blinding 
The study treatment is not blinded to the patient or the investigator. 
7.4 Information Collected on Screen Failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure.  The reason for not being started on treatment and eligibility 
information will be entered in the EDC system.    
7.5 Patient Demographics and Other Baseline Characteristics 
At screening/baseline, the following demographic and screening/baseline characteristic data will 
be collected from all patients:  
 Date of birth 
 Sex 
 Ethnicity 
 Race 
 Height 
 Weight 
 Systolic blood pressure 
 Diastolic blood pressure 
 ECOG performance status 
 Cystectomy eligibility status (if ineligible, record reason) 
 White blood cell count 
 Absolute neutrophil count 


 
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 Hemoglobin 
 Platelet count 
 Creatinine 
 AST 
 ALT 
 Total bilirubin 
 Alkaline phosphatase 
 Left ventricular ejection fraction 
 Charlson comorbidity index (CCI) 
The CCI for each patient is determined by summation of relative point values for each 
patient co-morbidity condition according to the following system: 
Conditions assigned 1 point each: 
 Myocardial infarct 
 Congestive heart failure 
 Peripheral vascular disease  
 Dementia 
 Cerebrovascular disease (CVA with mild or no residual effects or TIA) 
 Chronic lung disease 
 Connective tissue disease 
 Peptic ulcer 
 Mild chronic liver disease (i.e. without evidence of portal hypertension, includes 
chronic hepatitis) 
 Diabetes without end-organ damage (excludes diet-controlled alone) 
Conditions assigned 2 points each: 
 Hemiplegia 
 Moderate or severe kidney disease (GFR < 60 ml/min by Cockcroft-Gault 
formula) 
 Diabetes with end organ damage (i.e. retinopathy, neuropathy, nephropathy) 
 Any cancer (exclude if > 5 years from diagnosis with no active disease) 
 Leukemia (acute or chronic) 
 Lymphoma 
Conditions assigned 3 points each: 


 
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 Moderate or severe liver disease (i.e. with evidence of portal hypertension) 
  Conditions assigned 6 points each: 
 Metastatic solid organ cancer 
 AIDS 
For example, a patient with BCG-refractory urothelial carcinoma (2 pts), type 2 diabetes without 
end organ damage (1 pt), past history of a non-ST-elevation myocardial infarction (1 pt), with 
history of chronic obstructive pulmonary disease (1 pt) would have a CCI = 5. 
 Bladder tumor stage (Ta, Tis, T1, Ta + Tis, T1 + Tis) 
 Number of prior intravesical BCG courses (i.e. BCG x 2 courses → mitomycin C x 1 
course → gemcitabine x 1 course = 2 prior BCG courses) 
 Number of prior intravesical courses of any type (i.e. BCG x 2 courses → mitomycin C x 
1 course → gemcitabine x 1 course = 4 prior intravesical courses) 
 Number of prior intravesical agents received (i.e. BCG x 2 courses → mitomycin C x 1 
course → gemcitabine = 3 prior agents) 
 Date of last intravesical therapy of any kind 
 Date of last intravesical BCG therapy 
 Tumor FGFR3 mutation status 
 Tumor FGFR3 over-expression status  
7.6 Treatment Period 
All patients will be treated until either: 1) relapsed disease is noted; 2) Treatment related toxicity 
requiring a third dose reduction is encountered; 3) Treatment related toxicity not yet requiring a 
third dose reduction but per the treating physician’s discretion is deemed unsuitable for further 
dovitinib therapy is encountered; or 4) Patient electively foregoes further dovitinib therapy at any 
time.  
7.7 End of Treatment and Premature Withdrawal Visit 
Patients who discontinue study drug before completing the study should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the final visit will be 
performed.  The date and reason for stopping the study treatment will be recorded in the eCRF.  
At a minimum, all patients who discontinue study treatment, including those who refuse to return 
for a final visit, will be contacted for safety evaluations during the 30 days or 5 half-lives 
(whichever is longer) following the last dose of study drug. 
Patients who discontinue study treatment also should return for tumor assessments per the study 
calendar and should not be considered withdrawn from the study. If patients refuse to return for 
these visits or are unable to do so, every effort should be made to contact them or a 
knowledgeable informant by telephone to determine the date and tumor response status as well as 


 
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the date and tumor relapse status. Record the date and tumor response status as well as date and 
tumor relapse status in the eCRF.   
Patients who discontinue study drug should be considered withdrawn from the study after the 
final visit assessments are performed or when it is clear that the patient will not return for these 
assessments. 
If a withdrawal occurs, or if the patient fails to return for visits, the investigator must determine 
the primary reason for a patient’s premature withdrawal from the study and record this 
information in the eCRF. 
If a patient discontinues study drug, but continues study assessments, the reason for study 
completion should be recorded in the eCRF. 
End of treatment/Premature withdrawal visit is not considered as the end of the study.  
7.7.1 Criteria for Premature Patient Withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following occur:  
pregnancy; discovery of patient ineligibility; errors in treatment compliance [study drug, other 
prescribed 
or 
non-prescribed  
medications];  
missed/unscheduled/off-
schedule/incomplete/incorrect assessments. 
7.7.2 Follow-up for Toxicities  
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value must be followed at least once a week for 4 weeks, and subsequently 
at 4-week intervals, until resolution or stabilization of the event, whichever comes first. If a 
patient requires a dose delay of > 14 days from the intended day of the next scheduled dose, then 
the patient must be discontinued from the study. However, the patient will continue to be 
followed for toxicity as previously described. All patients will be followed for adverse events and 
serious adverse events for 30 days following the last dose of dovitinib. 
7.8 Replacement Policy 
Patients prematurely withdrawn within the first 3 months of therapy and prior to the first post-
therapy cystoscopy with urine cytology and TURBT will be replaced.  Patients prematurely 
withdrawn after their first post-therapy cystoscopy with urine cytology and TURBT will not be 
replaced.   
7.9 Follow up Period 
All patients must have safety evaluations for 30 days or 5 half-lives (whichever is longer) after 
the last dose of study treatment.  All patients will be followed for tumor relapse status until tumor 
relapse is noted or for 12 months beyond last dose of study treatment in patients who stopped 
dovitinib prior to disease relapse. 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 


 
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7.10 Assessment Types 
7.10.1 Demographics 
At baseline, demographic and baseline characteristic data will be collected from all patients. See 
section 7.5 for details.  
7.10.2 Diagnosis and Extent of Cancer 
7.10.2.1 Tumor Stage 
Bladder tumor stage will be defined according to the American Joint Commission on Cancer 
(AJCC) Staging system for bladder tumors (Edge SB et al., 2010).  T-stage classifications 
include: 
Tx – Primary tumor cannot be assessed 
T0 – no evidence of primary tumor 
Ta – Noninvasive papillary carcinoma which does not invade into the lamina propria 
Tis – Carcinoma in situ 
T1 – Tumor invades into the lamina propria but not into the muscularis propria 
T2a – Tumor invades into the inner half of the muscularis propria 
T2b – Tumor invades into the outer half of the muscularis propria 
T3a – Tumor microscopically invades the perivesical tissue 
T3b – Tumor macroscopically invades the perivesical tissue 
T4a – Tumor invades the prostatic stroma, uterus, or vagina 
T4b – Tumor invades into the pelvic wall, or abdominal wall 
7.10.2.2 Lymph Node Stage 
Bladder lymph node stage will be defined according to the American Joint Commission on 
Cancer (AJCC) Staging system for bladder tumors.(Edge SB et al., 2010)  N-stage classifications 
include: 
Nx – Lymph nodes cannot be assessed 
N0 – no lymph node metastasis 
N1 – Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external 
iliac, or presacral lymph node) 
N2 – Multiple regional lymph node metastases in the true pelvis (hypogastric, obturator, external 
iliac, or presacral lymph nodes) 
N3 – Lymph node metastases to the common iliac lymph nodes 


 
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7.10.2.3 Metastases Stage 
Bladder metastasis stage will be defined according to the American Joint Commission on Cancer 
(AJCC) Staging system for bladder tumors (Edge SB et al., 2010).  M-stage classifications 
include: 
M0 – No distant metastasis 
M1 – Distant metastasis 
7.10.3 Prior Anti-neoplastic Therapy 
At baseline, the following prior anti-neoplastic therapy characteristic data will be collected from 
all patients:  
 Number of prior intravesical BCG courses (i.e. BCG x 2 courses → mitomycin C x 1 
course → gemcitabine x 1 course = 2 prior BCG courses) 
 Number of prior intravesical courses of any type (i.e. BCG x 2 courses → mitomycin C x 
1 course → gemcitabine x 1 course = 4 prior intravesical courses) 
 Number and name of prior intravesical agents received (i.e. BCG x 2 courses → 
mitomycin C x 1 course → gemcitabine x 1 course = 3 prior agents) 
 Date of last intravesical therapy of any kind 
 Date of last intravesical BCG therapy 
7.10.4 Vital Signs 
At baseline and subsequent study visits, the following vital signs data will be collected from all 
patients:  
 Temperature (oC) 
 Heart rate (beats per minute) 
 Systolic blood pressure (mmHg) 
 Diastolic blood pressure (mmHg) 
 Respiratory rate (breaths per minute) 
 Height (cm) [only recorded at baseline] 
 Weight (kg)  
7.10.5 ECOG Performance Status 
At baseline and subsequent study visits, the Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) data will be collected from all patients.  The ECOG PS values are 
defined as follows:   
 ECOG 0 – Fully active, able to carry on all pre-disease performance without restriction 
 ECOG 1 – Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work  


 
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 ECOG 2 – Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
 ECOG 3 – Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
 ECOG 4 – Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair 
 ECOG 5 – Dead 
7.10.6 FGFR1, FGFR2, FGFR3, VEGFR1, VEGFR2, and VEGFR3 Mutation, Over-
expression, and Pathway Analyses 
7.10.6.1 FGFR3 Mutation Status 
Somatic FGFR3 mutations (see Table 1-2) in exons 7, 10, and 15 will be assessed in FFPE tumor 
tissues by massively parallel sequencing analysis utilizing the Ion Torrent Personal Genome 
Machine (PGM) and performed in the CLIA-certified Molecular Pathology and Translational 
Research Laboratory at the Dartmouth Hitchcock Medical Center.  
 
Unstained slides from the patients’ TURBT sample that was obtained within 42 days of 
registration will be submitted to two different laboratories prior to registration to determine 
FGFR3 mutation status and over-expression status. The laboratories will directly notify the site 
within 5-7 days, the results of the testing.  In cases where multiple biopsies were obtained, the 
site pathologist is asked to send slides from the biopsy with the highest grade and the greatest 
volume of tumor present within the biopsy sample.  Consider the biopsy results depicted below: 
 
Biopsy sample 
Location 
Diagnosis 
Tumor volume 
#1 
Dome 
Ta low-grade UC 
Tiny 
#2 
Rt Lateral wall 
T1 high-grade UC + CIS 
Moderate 
#3 
Left Lateral wall 
CIS 
Small 
#4 
Posterior wall 
T1 high-grade UC + CIS 
Large 
 
In the example above, the site pathologist would be asked to send slides from biopsy #4 from 
the posterior bladder wall. 
 
Consider the biopsy results below: 
 
Biopsy sample 
Location 
Diagnosis 
Tumor volume 
#1 
Dome 
Ta low-grade UC 
Tiny 
#2 
Rt Lateral wall 
CIS 
Moderate 
#3 
Left Lateral wall 
CIS 
Large 
#4 
Posterior wall 
No malignancy 
Large 
 
In the example above, the site pathologist would be asked to send slides from biopsy #3 from 
the left lateral bladder wall. 
 


 
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Consider the biopsy results below: 
 
Biopsy sample 
Location 
Diagnosis 
Tumor volume 
#1 
Dome 
Ta low-grade UC 
Tiny 
#2 
Rt Lateral wall 
T1 high-grade UC 
Moderate 
#3 
Left Lateral wall 
CIS 
Moderate 
#4 
Posterior wall 
No malignancy 
Large 
 
In the example above where there is the presence of both T1 high-grade UC and CIS residing in 
separate samples, the site pathologist would be asked to send slides from both biopsy #2 from 
the rt lateral bladder wall and biopsy #3 from the left lateral bladder wall. 
 
Refer to SPM for detailed collection, labeling and shipping guidelines. Upon receipt in the 
laboratory, each slide will be visually inspected for any signs of damage during shipment.  One 
H&E stained slide will be reviewed under light microscope to assess percent tumor cell content.  
A minimum of 40% tumor cell content is required in the entire tissue section; otherwise, 
macrodissection will be performed to ensure maximum tumor cell content. 
 
DNA will be isolated utilizing a standard commercially available extraction kit (i.e. Qiagen 
PureGene) according to manufacturer specifications.  FGFR3 mutational status will be 
determined by DNA sequencing of all coding exons including exons 7, 10, and 15.  Upon 
completion of testing, the presence/absence of an FGFR3 mutation (see Table 1-2) will be 
communicated to the treating site via email and /or fascimile. 
A whole blood sample will be collected at cycle 1 day 1. 
DNA from PBMC’s will be extracted using a standard commercially available DNA extraction 
kit (i.e. Qiagen DNeasy™).  FGFR3 single nucleotide polymorphisms (SNPs) in PBMC’s will be 
analyzed by commercially validated probes.  Refer to SPM for collection and shipping guidelines. 
7.10.6.2 FGFR3 Overexpression Status 
Presence of FGFR3 over-expression within tumor tissue will be assessed at study entry by the 
IUSCC’s IHC Core.  The IHC antibody used to determine FGFR3 over-expression is 
commercially available from Novus Biologicals. 
Refer to SPM for collection, labeling and shipping guidelines. 
 
Presence of FGFR3 over-expression within tumor tissue will be assessed and interpreted by two 
separate pathologists.  Brain, kidney, and testes are the recommended positive controls. Non 
specific immune serum will be used as the negative control. Staining intensity will be graded 0, 
+1, +2,+3 and ≥ +1 brown staining in the tissues defines positivity. Up to 3 pieces of tissue are to 
be analyzed at 3 to 5 high power fields if available. 
Upon completion of testing, the presence/absence of FGFR3 over-expression will be 
communicated to the treating site within 5-7 days.  


 
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7.10.6.3  FGFR1 and FGFR2 Mutation Status 
FGFR1 and FGFR2 single nucleotide polymorphisms (SNPs) in PBMC DNA extracted as 
described in 7.10.6.1 will be analyzed utilizing commercially validated probes.  In cases of scant 
PBMC DNA availability, FGFR3 analyses will take priority over FGFR1 and FGFR2 analyses. 
Refer to SPM for collection and shipping guidelines. 
7.10.6.4 VEGFR1, VEGFR2, and VEGFR3 Mutation Status 
A whole blood sample will be collected at cycle 1 day 1. 
DNA from PBMC’s will be extracted using a standard commercially available DNA extraction 
kit (i.e. Qiagen DNeasy™).  VEGFR1, VEGFR2, and VEGFR3 single nucleotide polymorphisms 
(SNPs) in PBMC’s will be analyzed by commercially validated probes.  Refer to SPM for 
collection and shipping guidelines. 
7.10.6.5 VEGFR Over-expression Status 
Presence of VEGFR1, VEGFR2, and VEGFR3 overexpression within tumor tissue will be 
assessed by the IUSCC’s IHC Core.   
Presence of VEGFR1, VEGFR2, and VEGFR3 over-expression within tumor tissue will be 
assessed and interpreted by standard immunohistochemistry analysis with appropriate controls.  
Refer to SPM for collection and shipping guidelines. 
 
7.10.6.6 FGFR and VEGFR Pathway Signaling Analyses 
Assessment of the effect of dovitinib on FGFR and VEGFR pathway signaling will be assessed 
by the IUSCC IHC Core through analysis of pre- and post-treatment TURBT specimens.   
All samples will be analyzed for FGFR3, pFGFR3, VEGFR2, pVEGFR2, FRS2, pFRS2, ERK, 
pERK by standard immunohistochemistry analysis with appropriate controls.  Where additional 
tissue is available, analysis of additional FGFR/VEGFR pathway markers will also be performed. 
Refer to SPM for collection and shipping guidelines.  
7.10.7 Cystoscopy, TURBT, and Urine Cytology Evaluations 
7.10.7.1 Cystoscopy and TURBT 
All patients must have an adequate staging cystoscopy and TURBT performed within 42 days 
prior to study registration.  In order to be considered adequate, the muscularis propria portion of 
the bladder wall must be present within at least one of the TURBT biopsies.  All patients will be 
re-evaluated for response by standard of care cystoscopy every 3 months ± 7 days (e.g. 3 month, 
6 month, 9 month, 12 month) during the first year of follow-up.  All patients will be re-evaluated 
for response by standard of care TURBT/biopsy every 3 months (e.g. 3 month, 6 month) ± 7 days 
during the first 6 months of follow-up.  At each of the follow-up TURBT/biopsy evaluations, 
biopsy tissue should be obtained from each of the following areas to ensure uniform disease 
evaluation and tissue acquisition: 
1. All previously documented baseline tumor sites 


 
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2. Bladder dome 
3. Anterior bladder wall 
4. Left lateral bladder wall 
5. Right lateral bladder wall 
6. Bladder trigone 
7. Any additional new suspicious bladder areas 
In the absence of recurrence at 1-year from study registration, cystoscopic surveillance and 
TURBT/biopsies are at the treating physician’s discretion. 
 
NOTE: Patients with residual non-invasive UC tumors with no component of carcinoma in situ 
(i.e. Ta, T1) at 3-month cystoscopy and TURBT are not considered relapses and will be permitted 
to continue on dovitinib therapy.  If the subsequent 6-month cystoscopy, TURBT, and urine 
cytology shows no evidence of any remaining urothelial carcinoma in such patients, they will be 
considered a complete response.  Patients with any component of carcinoma in situ (CIS) at 3-
month cystoscopy/TURBT will be considered relapses and will not continue on dovitinib 
therapy. Any non-invasive UC tumors (i.e. Ta, T1, Tis) at the 6-month or any subsequent 
cystoscopy/TURBT is considered relapsed disease.  Similarly progression to invasive UC tumors 
(T2-T4) at any time point is also considered relapsed disease and patients will not continue on 
dovitinib therapy. 
7.10.7.2 Urine Cytology 
All patients must have standard of care urine cytology obtained within 42 days prior to study 
registration.  All patients will be re-evaluated for response by standard of care urine cytology 
obtained every 3 months ± 7 days (e.g. 3 month, 6 month, 9 month, 12 month) during the first 
year of follow-up.  In the absence of recurrence at 1-year from study registration, additional urine 
cytology assessments are at the treating physician’s discretion. 
7.10.7.3 Urine Fluorescent In-Situ Hybridization 
Testing of urine by fluorescent in-situ hybridization (FISH) for recurrence is not required at any 
time point as part of this study.  The treating urologist may order commercial urine FISH testing 
(i.e. Urovysion®) at their own discretion.   
7.10.8 Radiographic Evaluations 
7.10.8.1 Abdomen and Pelvis CT scan 
All patients will have an abdomen and pelvis CT scan performed within 28 days prior to study 
registration.  Subsequent scans while on study and in follow-up are at the treating physician’s 
discretion. 


 
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7.10.8.2 Chest x-ray or Chest CT scan 
All patients will have a chest x-ray performed within 28 days prior to study registration.  A chest 
CT may be substituted for the required chest x-ray provided it is also performed within 28 days 
prior to study registration.  Subsequent x-rays and CT scans while on study and in follow-up are 
at the treating physician’s discretion. 
7.10.9 Cardiac Evaluations 
7.10.9.1 Left Ventricular Ejection Fraction 
All patients will have left ventricular ejection fraction assessed within 28 days prior to study 
registration by either a 2-D echocardiogram or MUGA scan.  Additional evaluations of left 
ventricular ejection fraction will be performed, as clinically indicated and at End of Treatment. 
7.10.9.2 Electrocardiogram 
All patients will have cardiac dysrhythmias and prior ischemic history assessed by 12-lead 
electrocardiogram within 28 days prior to study registration, at Cycle 1 Day 12 and Day 26, as 
clinically indicated in subsequent on-treatment cycles, and at End of Treatment. 
7.10.10 Correlative Studies 
7.10.10.1 Plasma FGFR3 Mutation Status 
Presence of FGFR3 mutation within circulating plasma will be assessed at baseline by the IUSCC 
TVC.  Peripheral blood for plasma isolation will be obtained at Cycle 1 Day 1.  
Plasma free RNA will be isolated utilizing a standard commercially available RNA extraction kit 
(i.e. QiaAmp™ Circulating Nucleic Acid Purification Kit).  As the quantity of circulating free 
plasma RNA is expected to be low (picogram to nanongram range), FGFR3 mutations within 
circulating free plasma RNA will be assessed utilizing PCR-amplification of the target regions 
and sequencing. Refer to SPM for collection and shipping guidelines. 
7.10.10.2 Urine FGFR3 Mutation Status 
Presence of FGFR3 mutation within exfoliated urine tumor cells will be assessed at Cycle 1 Day 
1 by the CLIA-certified Molecular Pathology and Translational Research Laboratory at the 
Dartmouth Hitchcock Medical Center.  A 30 ml urine sample will be obtained from each patient 
at Cycle 1 Day 1 (this sample is separate from the standard of care urine cytology sample).   
Presence of FGFR3 mutations (see Table 1-2) within patient urine will be assessed by massively 
parallel sequencing of exons 7, 10, and 15 utilizing the Ion Torrent PGM instrument. 
Refer to SPM for collection, processing and shipping guidelines. 
7.10.10.3 Tumor Dovitinib Pharmacokinetic Evaluation 
All patients will have a post-therapy dovitinib pharmacokinetic evaluation performed.  Bladder 
biopsy tissue for the dovitinib pharmacokinetic evaluation should be collected on cycle 3 day 26 
(± 7 days) at the time of the first post-dovitinib TURBT.  The biopsy tissue may be obtained from 
a bladder tumor region or from normal appearing urothelium.   


 
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Dovitinib tissue concentrations will be analyzed by mass spectroscopy and liquid 
chromatography methodologies developed specifically for this protocol by the IUSCC Clinical 
Pharmacology Analytical Core (CPAC). Refer to SPM for collection and shipping guidelines. 
7.10.11 Laboratory Studies 
7.10.11.1 Complete blood counts 
A complete blood count including Hemoglobin, WBC, platelets, and differential will be obtained 
from each patient within 14 days of registration, at cycle 1 day 1, cycle 1 day 12, cycle 1 day 26, 
cycle 2 day 12, cycle 2 day 26, on day 26 of all subsequent cycles, and at the end of study 
treatment. 
7.10.11.2 Chemistry Studies 
Serum chemistries including BUN, creatinine, total bilirubin, ALT, AST, GGT, alkaline 
phosphatase, albumin, total protein, calcium, sodium, magnesium, potassium, phosphorous, 
glucose, LDH, amylase, and lipase will be assessed in each patient within 14 days of registration, 
at cycle 1 day 1, cycle 1 day 12, cycle 1 day 26, cycle 2 day 12, cycle 2 day 26, on day 26 of all 
subsequent cycles, and at the end of study treatment. 
7.10.11.3 Lipid Profile Studies 
Serum total cholesterol, triglycerides, LDL, and HDL will be assessed in each patient within 14 
days of registration, at cycle 1 day 26, cycle 2 day 26, on day 26 of all subsequent cycles, and at 
the end of study treatment. 
7.10.11.4 Coagulation Studies 
PT/INR, PTT, and fibrinogen will be assessed in each patient within 14 days of registration, at 
cycle 2 day 26, and as clinically indicated for all subsequent cycles. 
7.10.11.5 Urine Studies 
Urine dipstick and urinalysis with specific gravity, pH, protein, blood, glucose, WBC, RBC, 
bacteria, and casts will be assessed in each patient within 14 days of registration. Urine dipstick 
must be negative for protein or, if documentation of +1 (+2 for patients with renal cell carcinoma) 
results for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured 
creatinine clearance ≥ 50 mL/min/1.73m
2 must be attained from a 24 hour urine collection. 
Additional urine dipstick and microscopic studies will be performed only as clinically indicated 
in subsequent treatment cycles. 
7.10.11.6 Thyroid Function Studies 
TSH, T3, and T4 will be assessed in each patient within 14 days of registration, on cycle 3 day 26 
(± 5 days), cycle 6 day 26 (± 5 days), and at the end of study treatment. 


 
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7.10.11.7 Cardiac Enzyme Studies 
CPK, CK-MB, and troponin (T or I) will be assessed in each patient within 14 days of 
registration and only as clinically indicated in subsequent treatment cycles. 
7.10.11.8 Pregnancy Testing Studies 
A serum pregnancy test will be assessed in female patients of child-bearing potential within 14 
days of registration and on day 26 (± 5 days) of all subsequent treatment cycles.  
7.10.12 Efficacy 
7.10.12.1 6-month Complete Response Rate (6-month CR rate) 
The 6-month complete response (CR) rate is defined as the proportion of patients treated with 
dovitinib with no evidence of any remaining urothelial carcinoma tumors of any T-stage 
(including Tis) present within the bladder as assessed by standard of care cystoscopic 
examination with TURBT and urine cytology performed at 6 months after initiation of study 
therapy.   
 
NOTE: Patients with residual non-invasive UC tumors with no component of carcinoma in situ 
(i.e. Ta, T1) at 3-month cystoscopy and TURBT are not considered relapses and will be 
permitted to continue on dovitinib therapy.  If the subsequent 6-month cystoscopy, TURBT, and 
urine cytology shows no evidence of any remaining urothelial carcinoma in such patients, they 
will be considered a complete response.  Patients with any component of carcinoma in situ (CIS) 
at 3-month cystoscopy/TURBT will be considered relapses and will not continue on dovitinib 
therapy. Any non-invasive UC tumors (i.e. Ta, T1, Tis) at the 6-month or any subsequent 
cystoscopy/TURBT is considered relapsed disease.  Similarly progression to invasive UC 
tumors (T2-T4) at any time point is also considered relapsed disease and patients will not 
continue on dovitinib therapy. 
 
7.10.12.2 Relapse Free Survival (RFS) 
Relapse Free Survival (RFS) is defined as the time from study registration until the occurrence of 
any of the following relapse events: 
1. Evidence of any component of CIS at 3-month cystoscopy/TURBT 
2. Recurrent tumor > T2 at any time point 
3. Recurrent tumor of any stage that occurs at or after the 6-month cystoscopy evaluation as 
assessed by bladder cystoscopy, TURBT, or urine cytology.  Note: While not required as 
part of the study follow-up testing, positive urine FISH test (even if an isolated finding) at 
or after the 6-month study evaluations will be considered relapsed disease. 
4. Documentation of metastatic urothelial carcinoma at any time point 


 
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7.10.12.3 1-year Relapse Free Survival (1-yr RFS) 
1-year RFS is defined as the proportion of patients who do not fulfill any of the relapse 
definitions in section 7.10.11.2 one year after study registration. 
7.10.12.4 Complete Response (CR) 
Complete response (CR) is defined as disappearance of all bladder tumors (of any T-stage), both 
grossly and microscopically on urine cytology and post-treatment bladder biopsy. 
7.10.12.5 Partial Response (PR) 
A partial response (PR) is defined as persistently present, but reduced bladder tumor T-stage on 
post-treatment bladder biopsy/TURBT in the absence of any new bladder tumors of any stage and 
in the absence of progression to muscle-invasive stage (i.e. > T2) of any previously documented 
bladder tumors.  A reduction in the number of bladder tumors but that retains the baseline T-stage 
does not qualify as a partial response.  The following is a list of partial response examples: 
T1  Ta 
T1 + Tis  T1 
T1 + Tis  Ta 
 Tis  Ta 
7.10.12.6 Progression to Muscle-Invasive Disease 
Progression to Muscle-Invasive disease is defined as the appearance of any tumor of > T2 at any 
time in follow-up. 
7.10.12.7 Progressive Disease (PD) 
Progressive Disease (PD) is defined as the appearance of any muscle-invasive (>T2) tumor, 
lymph node metastases (N1-3), or any metastases (M1) at any time in follow-up. 
7.10.12.8 Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence or non-protocol therapy is documented.   
7.10.12.9 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that relapsed or progressive disease is 
objectively documented. 
7.10.12.10 Duration of Complete Response 
The duration of CR is measured from the time measurement criteria are first met for CR until the 
first date that relapsed or progressive disease is objectively documented. 


 
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7.10.13 Safety and Tolerability 
Safety will be monitored by assessing the adverse events at every visit. For details on AE 
collection and reporting, refer to Section 8.  
8 Safety Monitoring and Reporting 
8.1 Adverse Events 
8.1.1 Definitions and Reporting 
An adverse event for the purposes of this protocol is defined as the appearance of (or worsening 
of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s).  
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, the severity 
of mild, moderate, severe, and life-threatening, or grades 1 - 4, will be used. CTCAE grade 5 
(death) will not be used in this study; rather, this information will be collected and recorded in the 
Adverse Events eCRF as end of treatment or survival information.  
Adverse events will be recorded from the time of consent and for at least 30 days after treatment 
discontinuation. All Adverse events considered related to trial medication will be followed until 
resolution, return to baseline, or deemed clinically insignificant, even if this occurs post-trial. 
Abnormal laboratory values or test results occurring after signing the informed consent form 
constitute adverse events only if they induce clinical signs or symptoms, or require therapy, (e.g., 
any hematologic abnormality that requires transfusion or hematological stem cell support) or 
changes in study medication(s) are considered clinically significant and should be recorded on the 
Adverse Events eCRF under the signs, symptoms or diagnosis associated with them. In addition, 
isolated abnormal laboratory values that are considered clinically significant (e.g., cause study 
discontinuation or constitutes in and of itself a Serious Adverse Event) should be recorded on the 
Adverse Events eCRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during the 
study. Adverse events also may be detected when they are volunteered by the patient (subject) 
during the screening process or between visits, or through physical examination, laboratory test, 
or other assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE grade 1-4)  
2. Causality to the adverse event (reasonable possibility that AE is related to dovitinib): (no, 
yes)  
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 


 
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5. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving,  
recovered/resolved with sequelae, fatal, unknown)  
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.  
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements, see Section 8.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; concomitant 
medication given; non-drug therapy given; patient hospitalized/patient’s hospitalization 
prolonged. The action taken to treat the adverse event should be recorded on the Adverse Event 
eCRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Disease progression should not be regarded or reported as an adverse event itself unless 
associated with a separate adverse event. 
Whenever possible, a diagnosis should be reported instead of underlying signs and symptoms. 
8.1.2 IND Safety Reports Unrelated to This Trial 
 
IND safety reports not occurring on this trial but involving the study intervention (outside SAEs) 
received from outside sources will be reviewed by the Sponsor Investigator and will be forwarded 
to participating sites for submission to their Institutional Review Boards per their guidelines.   
8.1.3 Laboratory Test Abnormalities 
8.1.3.1 Definitions and Reporting 
Abnormal laboratory values or test results that constitute adverse events or underlying conditions 
should not be reported separately in addition to the respective adverse events or underlying 
diagnosis. 
Additionally, laboratory abnormalities that are considered clinically significant due to induction 
of clinical signs or symptoms, or requiring concomitant therapy (e.g. any hematologic 
abnormality that requires transfusion or cytokine treatment) or changes in study medication(s), 
should be recorded on the Adverse Events eCRF. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory abnormalities 
that meet the criteria for adverse events should be followed until they have returned to normal or 
an adequate explanation of the abnormality is found. 
Laboratory abnormalities, that do not meet the criteria of clinical significance, as judged by the 
investigator, should not be reported as adverse events. A grade 3 or 4 event (severe) as per 
CTCAE does not automatically indicate a SAE unless it meets the definition of serious as defined 
below and/or as per investigator’s discretion. A dose hold or medication for the lab abnormality 


 
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may be required by the protocol in Section 6 and should not contribute to designation of a lab 
parameter abnormality as a SAE: 
8.2 Serious Adverse Events  
8.2.1 Definitions  
Serious adverse event (SAE) is defined as one of the following: 
 Is fatal or life-threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 Any SAEs that are expected due to the condition being treated, including if the SAE is a 
primary outcome measure, and whether there has been a clear agreement with regulators 
not to consider these as SAEs, provided the information is collected elsewhere 
 Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
8.2.2 Reporting 
To ensure patient safety, report every SAE, regardless of suspected causality, occurring 
 after the patient begins taking study drug and until at least 30 days after the patient has 
stopped study treatment 
Any SAEs experienced after this 30 days period should only be reported if the investigator 
suspects a causal relationship to the study drug. Recurrent episodes, complications, or progression 
of the initial SAE must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one should be reported 
separately as a new event. 


 
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Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form. 
The investigator must assess and record the relationship of each SAE to each specific study drug 
(if there is more than one study drug), complete the SAE Report Form, and send the completed, 
signed form to Hoosier Cancer Research Network (HCRN) within 1 business day of 
discovery of the event.    
Hoosier Cancer Research Network shall notify Novartis upon learning of the occurrence during 
the study.  Events will be reported to the oncology Novartis Integrated Medical Safety (IMS) 
department. All events must be reported, by FAX (877-778-9739), to Novartis 
Pharmaceuticals DS&E Department within 24 hours of learning of its occurrence along 
with Novartis SAE Report Fax Coversheet. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the 
case report form documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and is 
thought to be related to dovitinib, an oncology Novartis Integrated Medical Safety (IMS) 
department associate may urgently require further information from the investigator for Health 
Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
8.2.2.1 Study Center (Site) Requirements for Reporting SAEs 
Investigators and other site personnel must report any SAEs occurring during the course of the 
study within one business day of discovery of the event.  This includes events both related and 
unrelated to the investigational product.   
 
Related means that there is a reasonable possibility the drug caused the adverse experience. 
 
Unrelated The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event  may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
 
 
 


 
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The completed SAE Report Form (see SPM) must be faxed to Hoosier Cancer Research 
Network within 1 business day of discovery of the event.   The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the 
Trial Master File at the study site. 
Follow-up information will be faxed to Hoosier Cancer Research Network, using a new SAE 
Report Form stating that this is a follow-up to the previously reported SAE and giving the date 
of the original report. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how it was 
treated, and whether the patient continued or withdrew from study participation. 
8.2.2.2 Death and Immediately Life-Threatening Events  
 
Any death and immediately life-threatening event from any cause while a patient is receiving trial 
treatment on this protocol or up to 30 days after the last dose of trial treatment, or any death and 
immediately life-threatening event occurring more than 30 days after trial treatment has ended but 
which is felt to be treatment related must be reported within one business day of discovery of 
the event.  All deaths must be reported primarily for the purposes of SAE reporting; however, 
deaths due unequivocally to progression are not SAEs.   
 
Your local IRB should be notified and its reporting procedure followed.  The completed SAE 
Reporting Form should be faxed to Hoosier Cancer Research Network within one business day 
of discovery of the event. 
8.2.2.3 HCRN Requirements for Reporting SAEs 
 
Hoosier Cancer Research Network will report any possibly related SAE to Novartis within one 
business day of receipt of the SAE Reporting Form and to regulatory authorities (FDA) per 
federal requirements.   
 
Hoosier Cancer Research Network will fax a MedWatch to Novartis and will provide follow-up 
information as reasonably requested. 
8.3 Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to Novartis 
within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
 
Pregnancy should be recorded on a Clinical Study Pregnancy Form (see SPM) and reported to 
Hoosier Cancer Research Network within one business day of learning of its occurrence.  Hoosier 


 
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Cancer Research Network will report all pregnancies to the oncology Novartis Integrated Medical 
Safety (IMS) department. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study drug 
in this study. Consent to report information regarding these pregnancy outcomes should be 
obtained from the mother. 
8.4 Warnings and Precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated in 
the form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
8.5 Data and Safety Monitoring Plan 
As this is a small phase II trial of only 20 enrolled patients, a formal data and safety monitoring 
committee will not be employed.  However, the Hoosier Cancer Research Network data 
management team provides patient safety oversight for all Hoosier Cancer Research Network 
trials.  Specific data and safety monitoring tasks conducted by Hoosier Cancer Research Network 
include: 
 Review of clinical trials conducted for progress and safety 
 Review of all adverse events requiring expedited reporting as defined in the protocol 
 Review of reports generated by data quality control review process  
 Notification of the Sponsor Investigator and funding company of recommended 
action 
 Notification of sites coordinated by Hoosier Cancer Research Network of adverse events 
requiring expedited reporting and subsequent committee recommendations for study 
modifications 
In addition, Hoosier Cancer Research Network will compile data summary reports for this trial 
and submit these reports monthly to the Sponsor Investigator.  Hoosier Cancer Research Network 
will submit data summary reports to a Data Safety Monitoring Committee (DSMC) a minimum 
of twice per year for review. 
9 Data Review and Management 
9.1 Data Confidentiality 
Information about study patients will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed patient authorization informing the patient of the following:  
 What protected health information (PHI) will be collected from patients in this study 


 
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 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research patient to revoke their authorization for use of their PHI.  
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the patient is alive) at the end 
of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information.  Access to the system will be controlled by a sequence of individually assigned user 
identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
9.2 Site Monitoring 
All study sites will be monitored by Hoosier Cancer Research Network.  This includes on-site 
visits for prior to first study startup for new Hoosier Cancer Research Network sites and annual 
on-site visits for existing member sites.  Sites will be monitored for accuracy, timeliness, and 
completeness of data collection.  Hoosier Cancer Research Network will review source 
documents for verification of agreement with data submitted via the data collection system. The 
investigator/ institution guarantee access to source documents by Hoosier Cancer Research 
Network or its designee and appropriate regulatory agencies. In addition, adherence to protocols 
through evaluation of study deviations will be analyzed.   
The trial site may also be required to participate in a quality assurance audit by Novartis or its 
designee as well as inspection by appropriate regulatory agencies. 
It is important for the investigator and his/her relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
9.3 Data Handling and Record Collection 
9.3.1 Case Report Forms 
An electronic case report form (eCRF) is required and must be completed for each included 
patient.  The completed dataset is the sole property of Hoosier Cancer Research Network and 
should not be made available in any form to third parties, except for authorized representatives of 
appropriate Health/Regulatory Authorities, without written permission from Hoosier Cancer 
Research Network. 
9.4 Database Management and Quality Control 
Data will be entered into the study database by investigator/study coordinator for EDC studies. 
For studies using eCRFs, Hoosier Cancer Research Network personnel will review the data 
entered by investigational staff for completeness and accuracy. Detected discrepancies for which 
the resolution is obvious/self-evident will be corrected by Hoosier Cancer Research Network 


 
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Data Management personnel. Electronic data queries are stating the nature of the problem and 
requesting clarification will be created for all other discrepancies and missing values and sent to 
the investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Hoosier Cancer Research Network. 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the database has been declared to be complete and 
accurate, it will be locked and made available for data analysis.  
10 Statistical Methods and Data Analysis 
10.1 General Considerations 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at 
IUSM. Parameter estimates and relevant summary statistics will be reported for both efficacy and 
safety outcomes. Continuous variables will be summarized by means, medians, minima, maxima 
and standard deviations. Categorical variables will be summarized by frequencies and 
percentages. Missing data are expected to be rare. For patients that start therapy but do not make 
it to the primary endpoint evaluation, their 6-month status will be treated as not achieving CR. 
Consequently, our estimate of 6-month CR rate will be conservative. For secondary outcomes, 
missing data, if any, will not be imputed and complete-case analysis will be adopted. Additional 
exploratory analysis will be conducted when appropriate. Changes from the analysis plan will not 
require an amendment to the protocol unless it changes a significant feature in the protocol.  
10.2 Analysis Sets 
10.2.1 Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned.  
Patients will be analyzed according to the treatment they have been assigned to. 
10.2.2 Safety Set 
The Safety Set includes all patients who received at least one dose of study medication.  
10.2.3 Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who do not have 
significant deviations from the inclusion/exclusion criteria and are compliant with the treatment 
plan. 


 
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10.2.4 Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PAS) consists of all patients who have evaluable 
pharmacokinetic (PK) data from post-treatment bladder tissue. 
10.2.5 Efficacy Set 
The efficacy analysis set (EAS) consists of all patients who received at least one dose of study 
medication and had at least one post-treatment cystoscopy/TURBT and urine cytology 
performed.   
10.2.6 Other Analysis Sets  
Correlative analysis sets will consist of all patient sets who have evaluable correlative data for 
each proposed correlative analysis.  For instance, the plasma free FGFR3 mutation set will 
consist of all patients who have baseline plasma evaluable for FGFR3 mutation analysis. 
10.3 Patient Demographics/Other Baseline Characteristics 
Demographic and other baseline data (including disease characteristics and FGFR3 
mutation/over-expression status) will be summarized descriptively for all patients for the FAS.   
10.4 Treatments (Study Drug, Concomitant Therapies, Compliance) 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized for the safety set. 
10.4.1 Treatment Drug and Compliance 
Duration of treatment and compliance status will be tabulated for the safety set. 
10.4.2 Concomitant Therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized for the safety set. 
10.5 Primary Objective 
The primary objective of the trial is to determine the 6-month complete response rate in BCG-
refractory UC patients with FGFR3 mutant or over-expressing tumors treated with dovitinib. 
10.5.1 Primary Objective Statistical Considerations 
The 6-month complete response rate will be summarized by frequency and rate.  The one-sided 
90% confidence interval (CI) of Agresti-Coull type will be calculated for the rate.   
10.6 Secondary Objectives 
10.6.1 Key Secondary Objective(s) 
In addition to the study’s primary objective, key secondary objectives include: 


 
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 To determine the 1-year relapse free survival rate. 
 To determine the rate of progression to muscle-invasive stage (i.e. T2-T4). 
 To determine 3- and 6-month partial response rate defined as a reduction in T-stage on 
post-therapy TURBT (i.e. T1 ≥ Ta; T1+Tis ≥ Tis) 
 To characterize treatment related toxicity rates assessed by CTCAE v4.0 
10.6.2 Secondary Objectives Statistical Considerations 
All secondary objectives are hypothesis generating in nature.  One year RFS muscle-invasive 
progression, 3- and 6-month PR, and toxicity rates will be presented as rates and corresponding 
90% Agresti-Coull CIs.   
10.6.3 Safety Objectives 
10.6.3.1 Analysis Set and Grouping for the Analyses 
For all safety analyses, the safety set will be used.   
The overall observation period will be divided into three mutually exclusive segments:  
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication   
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication  
3. post-treatment period: starting at day 31 after last dose of study medication. 
10.6.3.2 Adverse Events (AE) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs.  However, all safety data (including 
those from the post-treatment period) will be listed and those collected during the pre-treatment 
and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTC grades), type of 
adverse event, and relation to the study drug.  Deaths reportable as SAEs and non-fatal serious 
adverse events will be listed by patient and tabulated by type of adverse event. 
Specific safety event categories (SEC) will be considered.  Such categories consist of one or more 
well-defined safety events which are similar in nature and for which there is a specific clinical 
interest in connection with the study treatment(s). 
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported. 
10.6.3.3 Laboratory Abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0, the study’s biostatistical and reporting team will grade laboratory data accordingly.  


 
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For laboratory tests covered by CTCAE, a grade 0 will be assigned for all non-missing values not 
graded as 1 or higher.  Grade 5 will not be used. 
In some cases (e.g. white blood cell differentials), the lower limits of normal ranges used in 
CTCAE definition may have to be replaced by a clinical meaningful limit expressed in absolute 
counts. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.  
The following summaries will be generated separately for hematology, biochemistry and urinary 
laboratory tests: 
 frequency table for newly occurring on-treatment grades 1, 2, 3 or 4 (see below for 
details) 
 shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
 for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
 listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.   
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots will be 
generated when appropriate. 
10.6.3.4 Other Safety Data 
ECG 
 shift table baseline to worst on-treatment result for overall assessments 
 lists of ECG evaluations for all patients with at least one abnormality. 
Vital Signs 
 shift table baseline to worst on-treatment result 
 table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
10.7 Exploratory Objectives 
In addition to the study’s primary and secondary objectives, key exploratory objectives include: 
 To characterize concordance rates between UC patient detected tumor, urine, and circulating 
free plasma FGFR3 mutations. 
 To characterize associations between pre-treatment germline (as assessed by PBMC 
extracted DNA) FGFR SNPs and post-treatment 6-month complete response rate and 1-year 
relapse free survival rate in patients treated with dovitinib. 


 
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 To characterize associations between pre-treatment germline (as assessed by PBMC 
extracted DNA) VEGFR SNPs and post-treatment 6-month complete response rate and 1-
year relapse free survival rate in patients treated with dovitinib. 
 To characterize VEGFR over-expression status within tumor tissue 
 To characterize pre- and post-treatment bladder tumor FGFR and VEGFR pathway 
phosphorylation changes as assessed by bladder tumor tissue immunohistochemistry. 
 To characterize post-treatment bladder tissue dovitinib concentrations. 
 To characterize associations between post-treatment hypertension, 6-month complete 
response rate and 1-year relapse free survival rate in patients treated with dovitinib. 
10.7.1 Exploratory Objectives Statistical Hypothesis, Model, and Method of 
Analysis 
All exploratory objectives are hypothesis generating in nature.  Pre- and post- treatment 
phosphorylation changes in FGFR and VEGFR pathways will be analyzed by paired t-tests.  
FGFR SNPs, VEGFR SNPs, post-treatment hypertension, and baseline clinical factors of interest 
(e.g. age, ECOG PS, Charlson Comorbidity Index, gender, T1 vs. CIS, number of prior 
intravesical therapies, etc.) will be analyzed by univariate logistic regression and Cox regression 
for significant associations with 6-month CR and 1-year RFS rates, respectively.  No multivariate 
models will be adopted given the small sample size.   Concordance rates between tumor, urine, 
and circulating free plasma FGFR3 mutations will be summarized by Goodman-Kruskal gamma.  
The post-treatment bladder tissue dovitinib concentrations will be summarized by mean, standard 
deviation, minimum, median, maximum, and boxplot. Transformations to normality will be 
considered when necessary.   
10.8 Sample Size Calculation 
The 6-month CR rate will be estimated with a one-sided 90% confidence interval of Agresti-
Coull type with the lower bound to be calculated and the upper bound set as 1. With an expected 
CR rate of ≥ 25%, a sample size of 20 patients will have a power of 0.80 to exclude a lower 
bound being ≤ 10%. 
 
Using a conservative estimate of FGFR3 mutation or over-expression present in 40% of BCG-
refractory tumors, 50 patients will need to be screened in order to enroll the required 20 patients 
on dovitinib therapy.   
 
The estimated accrual duration is 12 months and the estimated overall study duration is 2 years. 
10.9 Early Stopping Rules 
Early stopping rules will be performed after the first 10 patients have completed 3-month 
assessment for progression to T2 or greater stage based on TURBT samples.  The study will not 
be halted while the early stopping rule is being evaluated. 


 
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If the probability of the 3-month progression rate being no higher than 20% is lower than 0.1, it 
will be considered as unacceptable and the study will be closed.  Consequently, the trial would be 
stopped if 3-month progression is observed in 5 or more out of the first 10 patients. Note that the 
lower bounds of 90% Agresti-Coull confidence interval for 4, 5 and 6 out of 10 patients are 0.19, 
0.27, and 0.35, respectively. 
     
11 Ethical Considerations and Administrative Procedures 
11.1 Regulatory and Ethical Compliance 
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations 
(including European Directive 2001/20/EC and US Code of Federal Regulations Title 21), and 
with the ethical principles laid down in the Declaration of Helsinki. 
11.2 Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research Ethics 
Board (IRB/IEC/REB) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC/REB must be given to Novartis before 
study initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all of 
the instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs/REBs and regulatory authorities as required. 
11.3 Informed Consent Procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent <if applicable: or, if 
incapable of doing so, after such consent has been provided by a legally acceptable representative 
of the patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form>. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient source 
documents. 
Novartis will provide investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP guideline 
and regulatory requirements. Any changes to this ICF suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the approved 
version must be provided to the Novartis monitor after IRB/IEC/REB approval. 


 
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Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that in 
order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they should 
not be entered in the study. 
This study will include requesting patient consent to keep and store any leftover tissue samples in 
the Hoosier Cancer Research Network already established Biorepository for possible future IRB 
approved research. 
11.4 Discontinuation of the Study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4. 
11.5 Publication of Study Protocol and Results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicalstudys.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 Study Documentation, Record Keeping, and Retention of Documents 
To enable evaluations and/or audits from Health Authorities/Hoosier Cancer Research Network, 
the investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records; e.g., hospital records), all original signed informed consent 
forms, copies of all eCRF’s, and detailed records of drug disposition.  To comply with 
international regulations, the records should be retained by the investigator in compliance with 
regulations. 
 
During data entry, range and missing data checks will be performed on-line.  The checks to be 
performed will be documented in the Data Monitoring Plan for the study.  A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRF’s 
will be generated for each site and transmitted to the site and the site monitor.  Corrections will be 
made by the study site personnel.  This will be done on an ongoing basis. 
11.7 Confidentiality of Study Documents, and Patient Records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
11.8 Audits and Inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.  


 
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11.9 Financial Disclosures 
Financial disclosures should be provided by study personnel who is directly involved in the 
treatment or evaluation of patients at the site - prior to study start.  
12 Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis and 
approved by the IRB/IEC/REB it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the CSR. 
12.1 Amendments to the Protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the investigator 
is expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC/REB at the study site should be informed within 10 
working days. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (amended protocol) will be generated by Hoosier Cancer Research Network and 
must be approved by each IRB, Novartis, and if applicable, also the local regulatory authority.  
Local requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, then the IRB 
must be notified.  Approval of the revised Written Informed Consent Form by the IRB is required 
before the revised form is used.  
 
The Principal Investigator or his/her designee is responsible for the distribution of the protocol 
amendment and associated documents to his/her IRB, and to the staff at his/her center.  The 
distribution of these documents to the regulatory authority will be handled by the Principal 
Investigator or his/her designee according to local practice. 
Novartis’ willingness to supply study drug is predicated upon the review of the protocol.  Hoosier 
Cancer Research Network agrees to provide written notice to Novartis of any modifications to the 
protocol or informed consent. 


 
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