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

Novartis Pharmaceuticals38 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Solid Tumors Hepatic Impairment

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patients with histologically or cytologically confirmed solid tumor, excluding breast cancer, that is either refractory to the standard therapy or has no available therapies. 2. ECOG performance status (PS) 0 or 1 3. 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: 1. Patients with known brain metastases. 2. Patients who have undergone major surgery ≤ 4 weeks prior to starting study treatment Other protocol-defined inclusion/exclusion criteria may apply

Locations (12)

University of California at Los Angeles Dept. of UCLA (4)

Los Angeles, California, United States

Duke University Medical Center DUMC

Durham, North Carolina, United States

Cancer Therapy & Research Center / UT Health Science Center SC

San Antonio, Texas, United States

Novartis Investigative Site

Ghent, Belgium

Novartis Investigative Site

Frankfurt, Germany

Novartis Investigative Site

Hanover, Germany

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Rozzano, MI, Italy

Novartis Investigative Site

Verona, VR, Italy

Novartis Investigative Site

Amsterdam, Netherlands

...and 2 more locations

Outcomes

Primary Outcomes

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).

Time frame: 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).

Time frame: 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)

Time frame: 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)

Time frame: Day 1, Day 19

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, every 4 weeks