Dovitinib in BCG Refractory Urothelial Carcinoma With FGFR3 Mutations or Over-expression

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

Inclusion Criteria:

- Histologically confirmed early stage urothelial carcinoma of the bladder defined as
Ta, T1, or Tis stage.

- Presence of either an FGFR3 mutation or FGFR3 over-expression within bladder tumor
tissue.

- Documented BCG-refractory disease defined as failure to achieve a tumor free state
after at least 2 prior induction courses of intravesical BCG therapy.

- Medically unfit to undergo cystectomy or electively choosing to forego cystectomy

- Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

- 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.

- Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive
urothelial carcinoma.

- 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)

- 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

- Patients who have received prior VEGFR-targeted or FGFR-targeted agents (i.e.,
sunitinib, pazopanib, sorafenib, bevacizumab, axitinib, etc.).

- Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have
not recovered from radiotherapy toxicities

- 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

- Uncontrolled hypertension defined by a systolic blood pressure (SBP) ≥ 160 mm Hg
and/or d iastolic blood pressure (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 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

- Pregnant or breast-feeding women

- Women of child-bearing potential, who are biologically able to conceive, not employing
two forms of highly effective contraception. Highly effective contraception must be
used throughout the trial and up to 8 weeks after the last dose of study drug (e.g.
male condom with spermicidal; diaphragm with spermicide; intra-uterine device). Oral,
implantable, or injectable contraceptives that may be affected by cytochrome P450
interactions are not considered effective for this study. Women of child-bearing
potential, defined as 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.

- Fertile males not willing to use contraception, as stated above

- Patients unwilling or unable to comply with the protocol