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

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

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 Overview

• Status: Completed
• Conditions: Hepatic Impairment; Solid Tumors
• Intervention / Treatment: Drug: Dovitinib

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Novartis Investigative Site
• Germany
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37126
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
  • Maastricht, Netherlands, 5800
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Dept. of UCLA (4)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center DUMC
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy & Research Center / UT Health Science Center SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CTKI258A2124 from the Novartis Clinical Trials website

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: September 17, 2011
• First Submitted That Met QC Criteria: September 28, 2011
• First Posted (Estimate): September 29, 2011

Study Record Updates

• Last Update Posted (Actual): December 21, 2020
• Last Update Submitted That Met QC Criteria: December 17, 2020
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: pharmacokinetics; PK; solid tumors; hepatic impairment; Child-Pugh classification; RECIST 1.1
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: CTKI258A2124; 2011-000103-41 (EudraCT Number)