E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with either FGFR3 mutated or FGFR3 wild type advanced urothelial carcinoma |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To determine the Overall Response Rate (ORR) as per local radiological assessment in patients with FGFR3MUT advanced urothelial carcinoma treated with TKI258
• To determine the Overall Response Rate (ORR) as per local radiological assessment
in patients with (FGFR3WT) advanced urothelial carcinoma treated with TKI258 |
|
E.2.2 | Secondary objectives of the trial |
• To determine Overall Response Rate (ORR) as per central assessment in both groups
• To determine Progression Free Survival (PFS) as per local assessment and Overall Survival (OS) in both groups
• To assess Disease Control Rate (DCR) in both groups
• To characterize the safety and tolerability of TKI258 treatment |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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] (with or without metastases)
• Bilirubin ≤ 1.5 x ULN
• Serum creatinine ≤ 1.5 x ULN |
|
E.4 | Principal 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 three years prior to study entry, with the exception of adequately treated basal cell carcinoma , squamous cell carcinoma or non-melanomatous skin cancer, 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 ≤ 4 weeks prior to starting study drug, or who haven't 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 < 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan, < 45 % or lower limit of normal (whichever is higher)
• 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. Initiation or adjustment of antihypertensive medication(s) is allowed prior to study entry.
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 or equivalent anticoagulant (e.g. high dose aspirin or clopidogrel or other) or have an INR >1.5
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 compliance with the protocol
i. Pregnant or breast-feeding women
j. Women of child-bearing potential who are biologically able to conceive, and not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes thoroughout the trial and 8 weeks after the end of treatment. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore 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 have had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting TKI258. In instances.....
l. Cirrhosis, chronic active hepatitis or chronic persistent hepatitis |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate (ORR) is defined as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.0 (defined in Post-Text Supplement 1). ORR is assessed by local radiological review. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |