A Phase II multi-center, non-randomized, open-label study of TKI258 in patients with either FGFR3 mutated or FGFR3 wild type advanced urothelial carcinoma - N/A

Phase 1

Conditions: Patients with either FGFR3 mutated or FGFR3 wild type advanced urothelial carcinoma
MedDRA version: 12.0Level: LLTClassification code 10064467Term: Urothelial carcinoma

Registration Number: EUCTR2008-005870-11-NL

Lead Sponsor: ovartis Pharma Services AG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 0

Inclusion Criteria

1. Patients with histological confirmation of transitional cell carcinoma of the bladder,
urethra, ureter, or renal pelvis
• Locally advanced or metastatic disease
2. Archival tumor tissue available for Novartis designated FGFR3 mutational status analysis
3. Patients with documented progressive disease at baseline: progressive disease defined as
new or progressive lesions on cross-sectional imaging
4. Patients with at least one measurable site of disease as defined by RECIST criteria that has
not been previously irradiated
5. Previously treated with at least 1 but not more than 3 systemic cytotoxic regimens, with at
least one of these regimens including at least one of the following: cisplatin, carboplatin,
gemcitabine or taxane, administered in the perioperative or advanced setting and may have
been administered sequentially (e.g., first-line treatment followed by second-line treatment
at time of progression) or as part of a single regimen
6. Age = 18 years
7. WHO Performance Status = 2
8. Willing and able to take oral medication, comply with scheduled visits, treatment plan and
laboratory tests
9. Signed and witnessed informed consent form obtained prior to any screening procedures
10. Required baseline laboratory values:
• Absolute neutrophil count (ANC) = 1,500 cells/mm3 [SI units 1.5 x 109/L]
• Platelets = 100,000 cells/mm3 [SI units 100 x 109/L]
• Hemoglobin = 9.0 g/dL [SI units 90 g/L]
• AST/SGOT and ALT/SGPT = 3.0 x Upper Limit of Normal [ULN] (or AST/SGOT
and ALT/SGPT = 5 x ULN if abnormal liver function is due to tumor involvement of
the liver)
• Bilirubin = 1.5 x ULN
• Serum creatinine = 1.5 x ULN
• Potassium within normal limits
• Sodium within normal limits
• Total Calcium (corrected for serum albumin) within normal limits
• Magnesium within normal limits
• Phosphorus within normal limits
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Patients with known brain metastases or who have signs/symptoms attributable to brain
metastases and have not been assessed with radiologic imaging to rule out the presence of
brain metastases
2. Patients with history of another malignancy within the last five years prior to study entry,
except cured basal cell carcinoma of the skin, excised carcinoma in situ of the cervix, or
adenocarcinoma of the prostate that has been surgically treated with a post-treatment PSA
that is non-detectable
3. Patients who have received the last administration of an anti-cancer therapy, including:
chemotherapy, immunotherapy, hormonal therapy, and targeted therapy, but excluding:
nitrosourea, mitomycin-C, monoclonal antibodies, and radiation = 14 days prior to starting
study drug, or who have not recovered from side effects of such therapy
4. Patients who have received the last administration of nitrosourea or mitomycin-C = 6
weeks prior to starting study drug, or who have not recovered from the side effects of such
therapy
5. Patients who received the last administration of an anti-cancer monoclonal antibody = 6
weeks prior to starting study drug, or who have not recovered from the side effects of such
therapy
6. Patients who have received wide field radiotherapy (including therapeutic radioisotopes
such as strontium 89) = 4 weeks or limited field radiation for palliation = 2 weeks prior to
starting study drug, or who have not recovered from the side effects of such therapy
7. Patients who have undergone major surgery = 2 weeks prior to starting study drug, or who
have not recovered from the side effects of such therapy
8. Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study:
a. Impaired cardiac function or clinically significant cardiac diseases, including any of
the following:
• History or presence of serious uncontrolled ventricular arrhythmias or presence
of serious uncontrolled atrial fibrillation
• Clinically significant resting bradycardia
• LVEF, assessed by 2-D echocardiogram (ECHO) or multiple gated acquisition
scan (MUGA), < 45 %
• Any of the following within 6 months prior to study entry: 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 SBP = 160 mm Hg and/or DBP = 100
mm Hg, with or without anti-hypertensive medication
b. Previous pericarditis; clinically significant pleural effusion in the previous 12 months
or current ascites requiring two or more interventions/month
c. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter
the absorption of TKI258 (e.g. ulcerative diseases, uncontrolled nausea, vomiting,
diarrhea, malabsorption syndrome, or small bowel resection)
d. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is
not mandatory)
e. History of alcoholism, drug addiction, or any psychiatric or psychological condition
which, in the opinion of the investigator, would impair study compliance
f. Patients who are currently receiving anticoagulation treatment with therapeutic doses
of warfarin
g. Uncontrolled diarrhea = CTCAE grade 2
h. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
active or uncontrolled infection) that could cause unacceptable safety risks or
compromise com

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: • To determine the Overall Response Rate (ORR) as assessed by<br>Response Evaluation Criteria in Solid Tumors (RECIST) in patients with<br>(FGFR3MUT) advanced urothelial carcinoma treated with TKI258<br>• To determine the Overall Response Rate (ORR) as assessed by RECIST<br>in patients with (FGFR3WT) advanced urothelial carcinoma treated with<br>TKI258;Secondary Objective: • To determine Overall Response Rate (ORR) as per central assessment in<br>both groups<br>• To determine Progression Free Survival (PFS) and Overall Survival (OS)<br>in both groups<br>• To determine Disease Control Rate (DCR - Complete Response (CR),<br>Partial Response (PR) and Stable Disease (SD) =16 weeks after start of<br>TKI258 treatment) in both groups<br>• To characterize the safety and tolerability of TKI258 treatment;Primary end point(s): Overall Response (CR or PR) Rate. CR and PR will be defined according<br>to RECIST (defined in Post-Text Supplement 1) as per local assessment

Secondary Outcome Measures

Name	Time	Method

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