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

Study Overview
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Brief Summary
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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
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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

Official Title
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A Phase II Trial of Dovitinib in Bacillus Calmette-Guerin(BCG) Refractory Urothelial Carcinoma Patients With Tumor Fibroblast Growth Factor Receptor 3(FGFR3) Mutations or Over-expression: Hoosier Cancer Research Network GU12-157

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Dovitinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dovitinib<br>Dovitinib will be administered 500mg orally in a 5 days on, 2 days off dosing schedule. | Drug: Dovitinib<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine 6-Month Complete Response Rate | 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 transurethral resection of bladder tumor (TURBT) and urine cytology performed at 6 months after initiation of study therapy. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine 1-Year Relapse-Free Survival Rate | 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. | 12 months | 
| Determine Rate of Progression to Muscle-Invasive Stage | 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. | 12 months | 
| Determine 3-Month and 6-Month Partial Response Rates | 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). | 6 months | 
| Characterize Treatment-related Toxicity Rates | Treatment-related toxicity rates will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All grade 3-4 adverse events and other adverse events occurring in more than 20% of patients are reported. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dovitinib, FGFR3 Mutations, BCG-Refractory Urothelial Carcinoma