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