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

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ClinicalTrials.gov Identifier: NCT01732107
Recruitment Status : Terminated (Development of dovitinib was stopped.)
First Posted : November 22, 2012
Results First Posted : August 22, 2018
Last Update Posted : August 22, 2018
Sponsor:
Collaborators:
Novartis Pharmaceuticals
Hoosier Cancer Research Network
Information provided by (Responsible Party):
Noah Hahn, M.D., Hoosier Cancer Research Network

Tracking Information
First Submitted Date  ICMJE November 19, 2012
First Posted Date  ICMJE November 22, 2012
Results First Submitted Date  ICMJE July 25, 2018
Results First Posted Date  ICMJE August 22, 2018
Last Update Posted Date August 22, 2018
Actual Study Start Date  ICMJE March 2013
Actual Primary Completion Date March 6, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 19, 2012)
Determine 6-Month Complete Response Rate [ Time Frame: 6 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2018)
  • Determine 1-Year Relapse-Free Survival Rate [ Time Frame: 12 months ]
    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.
  • Determine Rate of Progression to Muscle-Invasive Stage [ Time Frame: 12 months ]
    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.
  • Determine 3-Month and 6-Month Partial Response Rates [ Time Frame: 6 months ]
    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).
  • Characterize Treatment-related Toxicity Rates [ Time Frame: 12 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2012)
  • Determine 1-Year Relapse-Free Survival Rate [ Time Frame: 12 months ]
    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.
  • Determine Rate of Progression to Muscle-Invasive Stage [ Time Frame: 12 months ]
    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.
  • Determine 3-Month and 6-Month Partial Response Rates [ Time Frame: 6 months ]
    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).
  • Characterize Treatment-related Toxicity Rates [ Time Frame: 12 months ]
    Treatment-related toxicity rates will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Current Other Pre-specified Outcome Measures
 (submitted: November 19, 2012)
  • Characterize Pre- and Post-treatment Bladder Tumor FGFR Pathway Phosphorylation Changes. [ Time Frame: 12 months ]
    Pre- and post-treatment bladder tumor FGFR pathway phosphorylation changes will be assessed by bladder tumor tissue immunohistochemistry utilizing commercially available antibodies including, but not limited to, the following: fibroblast growth factor receptors (FGFR3, pFGFR3), vascular endothelial growth factor receptors (VEGFR2, pVEGFR2), fibroblast growth factor receptor substrates (2FRS2, pFRS2), extracellular signal-regulated kinases (ERK), phosphorylated extracellular signal-related kinase (pERK).
  • Characterize Associations Between Pre-treatment Germline, 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. [ Time Frame: 12 months ]
    Pre-treatment germline FGFR SNPs will be assessed by testing extracted Deoxyribonucleic acid (DNA) from patient peripheral blood mononuclear cells (PBMC's) (collected prior to initiating dovitinib therapy) with validated commercial probes.
  • Characterize Pre- and Post-treatment VEGFR Pathway Phosphorylation Changes as Assessed by Bladder Tumor Tissue Immunohistochemistry. [ Time Frame: 12 months ]
    Pre- and post-treatment bladder tumor VEGFR pathway phosphorylation changes will be assessed by bladder tumor tissue immunohistochemistry utilizing commercially available antibodies including, but not limited to, the following: FGFR3, pFGFR3, VEGFR2, pVEGFR2, FRS2, pFRS2, ERK, pERK.
  • Characterize Associations Between Pre-treatment Germline VEGFR SNPs and Post-treatment 6-month Complete Response Rate and 1-year Relapse Free Survival Rate in Patients Treated With Dovitinib. [ Time Frame: 12 months ]
    Pre-treatment germline VEGFR SNPs will be assessed by testing extracted DNA from patient PBMC's (collected prior to initiating dovitinib therapy) with validated commercial probes.
  • Characterize Associations Between Post-treatment Hypertension, 6-month Complete Response Rate and 1-year Relapse Free Survival Rate in Patients Treated With Dovitinib. [ Time Frame: 12 months ]
    Hypertension will be defined as a systolic blood pressure (SBP) of > 140 mmHg or a diastolic blood pressure (DBP) of > 90 mm Hg recorded at any time after dovitinib therapy is initiated.
  • Characterize Concordance Rates Between UC Patient Detected Tumor, Urine, and Circulating Free Plasma FGFR3 Mutations. [ Time Frame: 12 months ]
    Presence of FGFR3 mutations within patient free plasma will be assessed by polymerase chain reaction (PCR) amplification of the target regions and sequencing.
  • Characterize Post-treatment Bladder Tissue Dovitinib Concentrations. [ Time Frame: 12 months ]
    Post-treatment bladder tissue dovitinib concentrations will be assessed by TURBT fresh frozen tissue obtained at the 3-month cystoscopy
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Dovitinib in BCG Refractory Urothelial Carcinoma With FGFR3 Mutations or Over-expression
Official Title  ICMJE 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
Brief 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.
Detailed Description

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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bladder Cancer
Intervention  ICMJE Drug: Dovitinib
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.
Study Arms  ICMJE Experimental: Dovitinib
Dovitinib will be administered 500mg orally in a 5 days on, 2 days off dosing schedule.
Intervention: Drug: Dovitinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: December 20, 2017)
13
Original Estimated Enrollment  ICMJE
 (submitted: November 19, 2012)
50
Actual Study Completion Date  ICMJE March 6, 2017
Actual Primary Completion Date March 6, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01732107
Other Study ID Numbers  ICMJE GU12-157
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Noah Hahn, M.D., Hoosier Cancer Research Network
Study Sponsor  ICMJE Noah Hahn, M.D.
Collaborators  ICMJE
  • Novartis Pharmaceuticals
  • Hoosier Cancer Research Network
Investigators  ICMJE
Study Chair: Noah Hahn, M.D. Hoosier Cancer Research Network
PRS Account Hoosier Cancer Research Network
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP