Predictive Value of Drug Elimination Gene Polymorphisms on Clearance and Dose Adjustment of Sunitinib in Cancer Patients (CLEARSUN)

Predictive Value of Drug Elimination Gene Polymorphisms on Clearance and Dose Adjustment of Sunitinib (Sutent, SU11248) in Patients With Cancer

Sunitinib is an anticancer drug, but like most drugs, the effect varies from person to person. This is partly due to a variation in how well each person eradicates the drug from the body. This can lead to toxicity if the drug is eliminated slowly. Just as important is inadvertent underdosing in people who eliminate the drug quickly which may lead to a reduced anti-cancer effect. The investigators group has developed a battery of tests that may measure how an individual clears a drug from their body. The investigators intend to apply these tests to a group of patients taking sunitinib to see whether any test will help predict the level of sunitinib in the body and also the side effects. If a test seems to be promising from this study it may be possible to do a simple test on patients before they receive sunitinib so the best dose is chosen. The tests involve identifying the genes that are involved with drug elimination (CYP3A, ABCB1, ABCG2, OCT1, OATP) as well as directly measuring elimination using marker drugs (midazolam clearance and sestamibi liver clearance).

Study Overview

• Status: Completed
• Conditions: Cancer

• Study Type: Observational
• Enrollment (Actual): 52

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Academic Medical Center Amsterdam
  • Rotterdam, Netherlands, 3075EA
    • Erasmus Medical Center, Daniel Den Hoed Cancer Center

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Patients with a malignancy treated with sunitinib

Description

Inclusion Criteria:

• Age >18
• A malignancy treated with single agent sunitinib
• ECOG 0, 1 or 2 at time of study accruement
• Any stable dose of therapy with sunitinib (defined as no dose change within 3 weeks prior to blood collection for pharmacokinetics)
• Adequate liver and renal function defined as serum bilirubin concentration less than 2 x ULN, AST and ALT less than 2.5 x ULN, serum creatinine concentration less than 2 x ULN
• No known primary liver disease and no other severe or uncontrolled concurrent medical condition within the first 3 months of treatment with sunitinib.
• Patients who have participated on other clinical studies of sunitinib will be suitable for this study.
• Signed informed consent
• Patients must not have Class ¾ cardiac problems as defined by the New York Heart Association criteria or any other severe or uncontrolled concurrent medical disease.
• Patients must not be pregnant or nursing and must be using an effective contraception method

Exclusion Criteria:

• Patients who are unable to sign informed consent
• Patients unable to give blood
• Patients with known midazolam allergies will not be included
• Patients must not be pregnant or nursing and must be using an effective contraception method
• Patients who had a bone-marrow-transplantation prior to sunitinib treatment
• Patients must not be taking routine systemic corticoid therapy
• Patients must not be taking therapeutic warfarin or warfarin derivates doses as anticoagulation at the time of study tests with an at least 2 weeks warfarin free period of time prior. Patients requiring anticoagulation may use low-molecular weight heparin

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Sunitinib; Patients with a malignancy treated with sunitinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To observe the correlation between ABCB1 polymorphisms in Exons 13, 22 and 27 and the clearance of sunitinib at steady state.	A blood sample will be drawn on day 1 of any treatment cycle and at steady state of the same cycle (between Day 21 and 28 inclusive)	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine whether ABCB1 genotype correlates with toxicity-adjusted dose of sunitinib	Toxicity adjustments will be collected within the first 3 months and correlated with the ABCB1 genotypes.	3 months
To determine the pharmacokinetics at steady state of the sunitinib treatment.	A blood sample will be drawn on day 1 of treatment cycle and at steady state of the same cycle (between Day 21 and 28 inclusive). The time of the blood collection are at day1 and in the 4th week: pre-drug administration then at 4 hours, 8 hours and 24 hours after drug intake.	4 weeks
To examine correlations between ABCB1 genotype and toxicity grade according to CTC criteria.	The toxicity data of the first 3 months of treatment will be collected.	3 months
To examine the correlation between genotype haplotype of other drug elimination genes, such as organic anion transporter proteins (OATP) and other biliary efflux proteins such as MRP2, BCRP with sunitinib clearance and toxicity adjusted dose.	Investigations of drugelimination and clearance taken with in the first 4 weeks of the study will be collected as well as the toxicity data and dose adjustments within the first 3 month of treatment.	3 months
Correlation of drug elimination phenotype test (sestamibi liver scan and Midazolam clearance) with sunitinib clearance	sestamibi liver scan and midazolam clearance test will be performed pre-treatment and at steady state (sometime between day 21-28)of study participation.	4 weeks

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Erasmus Medical Center; South West Sydney Local Health District

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: March 16, 2010
• First Submitted That Met QC Criteria: April 2, 2010
• First Posted (Estimate): April 5, 2010

Study Record Updates

• Last Update Posted (Estimate): July 12, 2012
• Last Update Submitted That Met QC Criteria: July 11, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: sunitinib; cancer; pharmacokinetics; pharmacogenomics; Patients who have a malignancy and are going to be treated with sunitinib; doseindividualism
• Other Study ID Numbers: HGWH0008