Dovitinib Lactate in Treating Patients With Refractory or Stage 0-I Bladder Cancer With FGFR3 Mutations or Overexpression

Status: Active

Description

This phase II trial studies how well giving dovitinib lactate works in treating patients with refractory or stage 0-I bladder cancer with fibroblast growth factor receptor 3 (FGFR3) mutations or overexpression. Dovitinib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed early stage urothelial carcinoma of the bladder defined as Ta, T1, or Tis stage; tumor staging must be confirmed by TURBT performed within 42 days prior to registration
  • Presence of either an FGFR3 mutation or FGFR3 over-expression within bladder tumor tissue. FGFR3 mutations in exons 7, 10, and 15 will be assessed by polymerase chain reaction (PCR)-single strand conformation polymorphism (PCR-SSCP) sequencing analysis utilizing the CertNDx® molecular grading assay performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified Predictive Biosciences™ laboratories; FGFR3 over-expression will be assessed by standard immunohistochemistry (IHC) analysis performed within the Indiana University Simon Cancer Center Immunohistochemistry (IHC) Core Lab
  • Documented BCG-refractory disease defined as failure to achieve a tumor free state after at least 2 prior induction courses of intravesical BCG therapy; NOTE: For patients with residual non-invasive tumors (i.e. Ta, T1, Tis) after an initial 6-week induction course of intravesical BCG therapy, a second induction course of intravesical BCG therapy is required; patients with persistent non-invasive tumors (i.e. Ta, T1, Tis) despite an initial 6-week and second induction intravesical BCG therapy course are considered BCG-refractory and, therefore, eligible for study; patients with non-invasive tumor recurrences (i.e. Ta, T1, Tis) after only an initial 6-week induction course of intravesical BCG therapy are considered BCG-resistant and not eligible for study until persistent non-invasive tumor (i.e. Ta, T1, Tis) is demonstrated after a second induction course of intravesical BCG therapy has been administered; there is no maximum limit on the number of prior BCG therapy courses; in addition, there is no maximum limit on the number of prior non-BCG intravesical therapy courses (i.e. gemcitabine, valrubicin, interferon, mitomycin C, etc.)
  • Medically unfit to undergo cystectomy or electively choosing to forego cystectomy
  • Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance status 0 or 1 or 2
  • White blood cell count (WBC) >= 3.0 K/mm^3
  • Absolute neutrophil count (ANC) >= 1.5 K/mm^3
  • Platelets >= 100 K/mm^3
  • Hemoglobin (Hgb) >= 9 g/dL
  • Serum total bilirubin: =< 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
  • 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 Cockroft-Gault equation
  • 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; the required radiographic imaging includes: * Abdomen/Pelvis – computed tomography (CT) scan * Chest – chest x-ray or CT scan
  • 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. prostate specific antigen [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 anticancer 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 targeted prior VEGFR 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
  • Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: * 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 ** Left ventricular ejection fraction (LVEF) assessed by 2-dimensional (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) ** Any of the following within 6 months prior to starting study drug: 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) ** Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic 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 anticoagulation 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 and not employing two forms of highly effective contraception; two forms of 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 spermicide; 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
  • Patients unwilling or unable to comply with the protocol

Locations & Contacts

Indiana

Indianapolis
Indiana University / Melvin and Bren Simon Cancer Center
Status: Active
Contact: Noah M. Hahn
Phone: 317-948-1186
Email: nhahn@iupui.edu

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Approved
Contact: Mario Alfredo Eisenberger
Phone: 410-614-3511
Email: eisenma@jhmi.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the 6-month complete response rate in Bacillus Calmette–Guérin (BCG)-refractory urothelial cancer (UC) patients with FGFR3 mutant or over-expressing tumors treated with dovitinib (dovitinib lactate).

SECONDARY OBJECTIVES:

I. To determine the 1-year relapse free survival rate in BCG-refractory UC patients treated with dovitinib.

II. To determine the rate of progression to muscle-invasive stage (i.e. T2-T4).

III. To determine 3- and 6-month partial response rate defined as a reduction in T-stage on post-therapy transurethral resection of the bladder tumor (TURBT) (i.e. T1 -> Ta; T1+Tis -> Tis).

IV. To characterize treatment related toxicity rates assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

TERTIARY OBJECTIVES:

I. To characterize pre- and post-treatment bladder tumor FGFR pathway phosphorylation changes.

II. To characterize associations between pre-treatment germline (as assessed by peripheral blood mononuclear cells [PBMC] extracted deoxyribonucleic acid [DNA]) FGFR single nucleotide polymorphisms (SNPs) and post-treatment 6-month complete response rate and 1-year relapse free survival rate in patients treated with dovitinib.

III. To characterize pre- and post-treatment vascular endothelial growth factor receptor (VEGFR) pathway phosphorylation changes as assessed by bladder tumor tissue immunohistochemistry.

IV. To characterize associations between pre-treatment germline (as assessed by PBMC extracted DNA) VEGFR SNPs and post-treatment 6-month complete response rate and 1-year relapse free survival rate in patients treated with dovitinib.

V. To characterize associations between post-treatment hypertension, 6-month complete response rate and 1-year relapse free survival rate in patients treated with dovitinib.

VI. To characterize concordance rates between UC patient detected tumor, urine, and circulating free plasma FGFR3 mutations.

VII. To characterize post-treatment bladder tissue dovitinib concentrations.

OUTLINE:

Patients receive dovitinib lactate orally (PO) once daily (QD) five days a week. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 12 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Hoosier Oncology Group

Principal Investigator
Noah M. Hahn

Trial IDs

Primary ID GU12-157
Secondary IDs NCI-2013-00610, CTKI258AUS17T, 1211009949
Clinicaltrials.gov ID NCT01732107