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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Hoosier Cancer Research Network
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Hoosier Cancer Research Network
ClinicalTrials.gov Identifier:
NCT01732107
First received: November 19, 2012
Last updated: June 30, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Bladder Cancer
Drug: Dovitinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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 Oncology Group GU12-157

Resource links provided by NLM:


Further study details as provided by Hoosier Cancer Research Network:

Primary Outcome Measures:
  • Determine 6-Month Complete Response Rate [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Determine 1-Year Relapse-Free Survival Rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    Treatment-related toxicity rates will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0


Other Outcome Measures:
  • Characterize pre- and post-treatment bladder tumor FGFR pathway phosphorylation changes. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Post-treatment bladder tissue dovitinib concentrations will be assessed by TURBT fresh frozen tissue obtained at the 3-month cystoscopy


Estimated Enrollment: 50
Study Start Date: March 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dovitinib
Dovitinib will be administered 500mg orally in a 5 days on, 2 days off dosing schedule.
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.

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
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01732107

Contacts
Contact: Noah Hahn, M.D. (317) 948-1186 nhahn@iupui.edu
Contact: Cynthia Burkhardt, R.N. (317) 9212050 gegould@iupui.edu

Locations
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Costantine Albany, M.D.    317-278-1711    calbany@iu.edu   
Contact: Kerry Bridges    317-274-2552    kdbridge@iupui.edu   
United States, Maryland
Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21231
Contact: Mario Eisenberger, M.D.    410-614-3511      
Contact: Linnea Smith-Walters    410.502.0017    lsmithw1@jhmi.edu   
United States, Pennsylvania
Fox Chase Cancer Center Extramural Research Program Recruiting
Rockledge, Pennsylvania, United States, 19046
Contact: Richard Greenberg, M.D.    215-728-2769    Richard.Greenberg@fccc.edu   
Contact: Trish O'Brien       Trish.OBrien@fccc.edu   
Sponsors and Collaborators
Hoosier Cancer Research Network
Novartis Pharmaceuticals
Investigators
Study Chair: Noah Hahn, M.D. Hoosier Cancer Research Network
  More Information

Additional Information:
No publications provided

Responsible Party: Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT01732107     History of Changes
Other Study ID Numbers: GU12-157
Study First Received: November 19, 2012
Last Updated: June 30, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Hoosier Cancer Research Network:
Dovitinib
FGFR3 Mutations
BCG-Refractory Urothelial Carcinoma

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Carcinoma
Carcinoma, Transitional Cell
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on August 01, 2014