Pharmacokinetics (PK) of TKI258 in Cancer Patients With Normal and Impaired Hepatic Function

Study Overview
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Brief Summary
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This is a multi-center, open label study to assess pharmacokinetics (PK) of TKI258 at single-dose and steady state in adult cancer patients either with mild, moderate or severe hepatic impairment or with normal hepatic function. Hepatic function in study patients will be categorized as normal, mild, moderate or severe based upon pre-dose (Day 1) total bilirubin and AST/ALT levels. Starting dose of TKI258 will depend on total bilirubin and ALT/AST levels at baseline. Patients will be treated until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from the study treatment for any other reason.

Official Title
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A Multi-center, Open Label Study to Assess Pharmacokinetics of TKI258 in Adult Cancer Patients With Normal and Impaired Hepatic Function

Conditions
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Solid Tumors, Hepatic Impairment

Intervention / Treatment
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* Drug: Dovitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically or cytologically confirmed solid tumor, excluding breast cancer, that is either refractory to the standard therapy or has no available therapies. ECOG performance status (PS) 0 or 1 Patients must have measurable and/or non-measurable lesion(s) as assessed by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI) per RECIST 1.1 Exclusion Criteria: Patients with known brain metastases. Patients who have undergone major surgery ≤ 4 weeks prior to starting study treatment Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TKI258 normal hepatic function<br>TKI258 Capsule, @ 500 mg p.o. o.d. 5 days on/2 days off | Drug: Dovitinib<br>* Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups<br>* Other names: TKI258;|
| Experimental: TKI258 mild hepatic impairment<br>TKI258 capsule @ 500 or 400 mg p.o. o.d. 5 days on/2 days off | Drug: Dovitinib<br>* Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups<br>* Other names: TKI258;|
| Experimental: TKI258 moderate hepatic impairment<br>TKI258 capsule @ starting dose at 400 mg p.o. o.d. 5 days on/2 days off | Drug: Dovitinib<br>* Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups<br>* Other names: TKI258;|
| Experimental: TKI258 severe hepatic impairment<br>TKI258 capsule Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups | Drug: Dovitinib<br>* Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups<br>* Other names: TKI258;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) parameter of Cmax following a single dose of TKI258 and at the steady state | Cmax will be evaluated after a single dose of TKI258 and at the steady state following a 5 days on/2 days off dosing schedule. Cmax is the maximum (peak) plasma, blood, serum, or other body fluid drug concentration after a single dose administration (mass x volume - 1). | Day 1, Day 19 | 
| Pharmacokinetic (PK) parameter of Tmax following a single dose of TKI258 and at the steady state | Tmax will be evaluated after a single dose of TKI258 and at the steady state following a 5 days on/2 days off dosing schedule. Tmax is the time to to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after a single dose administration (mass x volume - 1). | Day 1, Day 19 | 
| Pharmacokinetic (PK) parameter of AUClast following a single dose of TKI258 and at steady state | AUClast will be evaluated after a single dose of TKI258 and at the steady state following a 5 days on/2 days off dosing schedule. AUC from time zero to the last measurable concentration sampling time t(last) (mass x time x volume^-1) | Day 1, Day 19 | 
| Pharmacokinetic (PK) parameter of AUCinf following a single dose of TKI258 | AUCinf is the time to zero to infinity (mass x time x volume) | Day 1, Day 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events and Serious Adverse Events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) | The Common Terminology Criteria for Adverse Events (AE) is a descriptive terminology which can be utilized for AE reporting. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of a treatment. | Baseline and every 4 weeks | 
| Change from Baseline in Vital Signs | Body temperature, sitting pulse rate, and sitting blood pressure will be measured at each visit. Blood Pressure (BP) will be measured according to the National Institute of Health, National Hart, Lung and Blood Institute Guidelines with following standardized techniques: patients are seated; BP measurement begins after at least 5 minutes of rest, the appropriate cuff size is used , measurements will be taken preferably with a mercury sphygmomanometer. If the BP reading is ≥ 160mm Hg systolic and/or ≥100 mmHg diastolic, repeat the measurement to verify initial reading. | Baseline, Weeks 1, 4, 5, 9 and once every 8 weeks thereafter | 
| Best overall response to anti-tumor activity of TKI258 through imaging as per RECIST 1.1 | RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve (respond), stay the same (stable) or worsen (progression) during treatments. | Every 8 weeks | 
| Change from Baseline in Electrocardiogram | A standard 12 lead Electrocardiogram(ECG)will be used. In order for an accurate evaluation of baseline QTc, a total of three 12-lead ECGs will be performed within 72 hours prior to the first dose of TKI258 administration on Week 1, Day 1. All ECGs will be transmitted to a central laboratory and will be centrally reviewed by an independent reviewer. | Baseline, Weeks 1, 4, 5 | 
| Pharmacokinetics and Hepatic Function Abnormalities | Exploration of the relationship between Pharmacokinetics (PK) and hepatic functional abnormalities (i.e. bilirubin, ALT/AST, and Child-Pugh classification using regression analysis as appropriate. | Baseline, every 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, hepatic impairment, Child-Pugh classification, pharmacokinetics, PK, RECIST 1.1