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

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.

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

Eligibility Criteria:
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