Explore the Synergy of Combination TKI Therapy

Explore the Synergy of Combination TKI Therapy - A Pilot Study to Evaluate the Effect of Imatinib on Dasatinib Pharmacokinetics in Healthy Volunteers

This research study is looking at how imatinib affects how dasatinib is absorbed and eliminated from the body. Both imatinib and dasatinib are in a class of medications called tyrosine kinase inhibitors (TKI) and they are used to treat certain types of leukemia (cancer that begins in the white blood cells). Both imatinib and dasatinib have been given safely in healthy volunteers. In this study investigators will evaluate the pharmacokinetics interaction between imatinib and dasatinib when they are co-administered. The hypothesis is that imatinib will increase the blood levels of dasatinib through inhibiting the drug metabolizing enzyme and efflux transporter that are involved in the dasatinib absorption and removal. This research will provide important new insight of combination TKI therapy in terms of transporter- and enzyme- mediated pharmacokinetic interactions. The research results will also help guide doctors in knowing how much of a tyrosine kinase inhibitor to give safely while reaching best effect in TKI combination therapy.

Study Overview

• Status: Withdrawn
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Dasatinib; Drug: Dasatinib+Imatinib

Detailed Description

If the subjects qualify to take part in this research study, they will undergo the following procedures.

Subjects will be asked to abstain from alcoholic beverages (24 hours), grapefruit products, herbal supplements/teas, and over-the-counter medications (48 hours) prior to the study visits. There will be two study periods in this study. During each period all the subjects are outpatients and there will be no overnight stay. During each study period, the subjects will come to the University of Florida Clinical Research Center (UF CRC) three times: on Day -1, Day 1, and Day 2, respectively. Subjects will report to the UF CRC the day before Day 1 (i.e. Day -1) to have clinical lab test and urine pregnancy test (female only). Subjects will come to UF CRC at 6:30 a.m. on Day 1 and Day 2 of each study visit. During the morning of each study period (around 8:30 am) subjects will be randomly assigned to receive a single oral dose of dasatinib 20 mg either with or without a single oral dose of imatinib 400 mg administered one hour prior to dasatinib. After the first study visit, the subjects will return one to two weeks later for the second study visit, receiving the opposite treatment. The treatment order for the study visits will be assigned randomly. The end point measures for this study are plasma concentrations of dasatinib. A total of twelve (12) blood samples will be collected for a total amount of 84 ml (about 3 ounces or about 6 tablespoonsful) for each subject during each study period.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• under healthy condition
• Non-smokers (self-reported) age 18 -55 years
• Body Mass Index (BMI) between 18 to 30 kg/m2 inclusive
• Signed Informed Consent

Exclusion Criteria:

• Any evidence of renal dysfunction (estimated creatinine clearance < 80ml/min).
• Any evidence of impaired hepatic function (liver enzymes greater than two times the upper limit of normal or total bilirubin > 2.0 mg/dL).
• Taking any medications other than oral contraceptives or hormonal replacement therapy.
• Use of any known inhibitor or inducer of CYP3A or P-gp within 30 days prior to study drug administration.
• Consumption of alcohol, grapefruit, star fruit, grapefruit products or star fruit products within the 72-hour period prior to study drug administration.
• Women who are pregnant or currently breastfeeding.
• Donation or loss of 550 mL or more blood volume (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to initial study drug administration.
• Known adverse effect or intolerance to imatinib or dasatinib.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Dasatinib; In this group, subjects will take dasatinib only. Dose regimen: dasatinib 20 mg single oral dose	Drug: Dasatinib; In this group, subjects will take dasatinib only. Dose regimen: dasatinib 20 mg single oral dose; Other Names: Sprycel
Active Comparator: Dasatinib+Imatinib; In this group, subjects will take imatinib prior to dasatinib administration. Dose regimen: Imatinib: 400 mg single oral dose Dasatinib: 20 mg single oral dose	Drug: Dasatinib+Imatinib; In this group, subjects will take imatinib prior to dasatinib administration. Dose regimen: Imatinib: 400 mg single oral dose Dasatinib: 20 mg single oral dose; Other Names: Other names of Dasatinib: Sprycel; Other names of Imatinib: Gleevec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under the plasma concentration versus time curve (AUC) of dasatinib	0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 15, and 24 hours post-dose

Collaborators and Investigators

• Sponsor: University of Florida
• Investigators: Principal Investigator: Guohua An, MD, PhD, University of Florida

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: April 30, 2014
• First Submitted That Met QC Criteria: April 30, 2014
• First Posted (Estimate): May 2, 2014

Study Record Updates

• Last Update Posted (Estimate): October 6, 2014
• Last Update Submitted That Met QC Criteria: October 3, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate; Dasatinib
• Other Study ID Numbers: IRB201400056