dovitinib in bcg refractory urothelial carcinoma with fgfr3 mutations or over-expression

Conditions: Bladder Cancer

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.

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

Keywords: dovitinib fgfr3 mutations bcg-refractory urothelial carcinoma