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

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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Bladder Cancer	Drug: Dovitinib	Phase 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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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 Cancer Research Network GU12-157
• Actual Study Start Date: March 2013
• Actual Primary Completion Date: March 6, 2017
• Actual Study Completion Date: March 6, 2017

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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).
4. 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.

Other Outcome Measures:

1. 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).
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

United States, Indiana

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States, 46202

United States, Maryland

Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States, 21231

United States, Pennsylvania

Fox Chase Cancer Center Extramural Research Program

Rockledge, Pennsylvania, United States, 19046

Sponsors and Collaborators

Noah Hahn, M.D.

Novartis Pharmaceuticals

Hoosier Cancer Research Network

Investigators

• Study Chair: Noah Hahn, M.D.; Hoosier Cancer Research Network

  Study Documents (Full-Text)

Documents provided by Noah Hahn, M.D., Hoosier Cancer Research Network:

Study Protocol and Statistical Analysis Plan  [PDF] July 9, 2014

More Information

Additional Information:

Hoosier Oncology Group Website 

• Responsible Party: Noah Hahn, M.D., Sponsor-Investigator, Hoosier Cancer Research Network
• ClinicalTrials.gov Identifier: NCT01732107
• Other Study ID Numbers: GU12-157
• First Posted: November 22, 2012
• Results First Posted: August 22, 2018
• Last Update Posted: August 22, 2018
• Last Verified: July 2018

Keywords provided by Noah Hahn, M.D., Hoosier Cancer Research Network:

Dovitinib; FGFR3 Mutations; BCG-Refractory Urothelial Carcinoma

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Transitional Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms