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

Primary Purpose

Solid Tumors, Hepatic Impairment

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Dovitinib
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Solid Tumors focused on measuring solid tumors, hepatic impairment, Child-Pugh classification, pharmacokinetics, PK, RECIST 1.1

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California at Los Angeles Dept. of UCLA (4)
  • Duke University Medical Center DUMC
  • Cancer Therapy & Research Center / UT Health Science Center SC
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

TKI258 normal hepatic function

TKI258 mild hepatic impairment

TKI258 moderate hepatic impairment

TKI258 severe hepatic impairment

Arm Description

TKI258 Capsule, @ 500 mg p.o. o.d. 5 days on/2 days off

TKI258 capsule @ 500 or 400 mg p.o. o.d. 5 days on/2 days off

TKI258 capsule @ starting dose at 400 mg p.o. o.d. 5 days on/2 days off

TKI258 capsule Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups

Outcomes

Primary Outcome Measures

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).
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).
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)
Pharmacokinetic (PK) parameter of AUCinf following a single dose of TKI258
AUCinf is the time to zero to infinity (mass x time x volume)

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
September 17, 2011
Last Updated
December 17, 2020
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01443481
Brief Title
Pharmacokinetics (PK) of TKI258 in Cancer Patients With Normal and Impaired Hepatic Function
Official Title
A Multi-center, Open Label Study to Assess Pharmacokinetics of TKI258 in Adult Cancer Patients With Normal and Impaired Hepatic Function
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
November 2011 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Solid Tumors, Hepatic Impairment
Keywords
solid tumors, hepatic impairment, Child-Pugh classification, pharmacokinetics, PK, RECIST 1.1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
38 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TKI258 normal hepatic function
Arm Type
Experimental
Arm Description
TKI258 Capsule, @ 500 mg p.o. o.d. 5 days on/2 days off
Arm Title
TKI258 mild hepatic impairment
Arm Type
Experimental
Arm Description
TKI258 capsule @ 500 or 400 mg p.o. o.d. 5 days on/2 days off
Arm Title
TKI258 moderate hepatic impairment
Arm Type
Experimental
Arm Description
TKI258 capsule @ starting dose at 400 mg p.o. o.d. 5 days on/2 days off
Arm Title
TKI258 severe hepatic impairment
Arm Type
Experimental
Arm Description
TKI258 capsule Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups
Intervention Type
Drug
Intervention Name(s)
Dovitinib
Other Intervention Name(s)
TKI258
Intervention Description
Starting dose to be determined based on the study outcome of the mild and moderate hepatic impairment groups
Primary Outcome Measure Information:
Title
Pharmacokinetic (PK) parameter of Cmax following a single dose of TKI258 and at the steady state
Description
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
Title
Pharmacokinetic (PK) parameter of Tmax following a single dose of TKI258 and at the steady state
Description
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
Title
Pharmacokinetic (PK) parameter of AUClast following a single dose of TKI258 and at steady state
Description
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
Title
Pharmacokinetic (PK) parameter of AUCinf following a single dose of TKI258
Description
AUCinf is the time to zero to infinity (mass x time x volume)
Time Frame
Day 1, Day 19
Secondary Outcome Measure Information:
Title
Frequency of Adverse Events and Serious Adverse Events as assessed by Common Terminology Criteria for Adverse Events (CTCAE)
Description
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
Title
Change from Baseline in Vital Signs
Description
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
Title
Best overall response to anti-tumor activity of TKI258 through imaging as per RECIST 1.1
Description
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
Title
Change from Baseline in Electrocardiogram
Description
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
Title
Pharmacokinetics and Hepatic Function Abnormalities
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
University of California at Los Angeles Dept. of UCLA (4)
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Duke University Medical Center DUMC
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cancer Therapy & Research Center / UT Health Science Center SC
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Novartis Investigative Site
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
Novartis Investigative Site
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20133
Country
Italy
Facility Name
Novartis Investigative Site
City
Rozzano
State/Province
MI
ZIP/Postal Code
20089
Country
Italy
Facility Name
Novartis Investigative Site
City
Verona
State/Province
VR
ZIP/Postal Code
37126
Country
Italy
Facility Name
Novartis Investigative Site
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Maastricht
ZIP/Postal Code
5800
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Singapore
ZIP/Postal Code
119228
Country
Singapore

12. IPD Sharing Statement

Links:
URL
https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=13906
Description
Results for CTKI258A2124 from the Novartis Clinical Trials website

Learn more about this trial

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

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