The Influence of Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib in Cancer Patients

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Sunitinib; Drug: Midazolam; Other: Grapefruit juice; Other: Orange juice

• Registration Number: NCT01743300
• Lead Sponsor: Leiden University Medical Center

Brief Summary

In this prospective pharmacokinetic we investigate the following topics:

* The influence of grapefruit juice and orange juice on the steady-state pharmacokinetics of sunitinib in cancer patients

* The influence of sunitinib on the pharmacokinetics of midazolam in cancer patients

* The relationship between Cytochrome-P450-3A4 (CYP3A4) phenotype, as assessed using the midazolam clearance test, and the steady-state pharmacokinetics of sunitinib in cancer patients

* The effect of grapefruit juice and orange juice on CYP3A4 metabolism

Detailed Description

This is a prospective pharmacokinetic study in two groups of 10 adult patients with imatinib-resistant gastro-intestinal stromal cell tumor or metastatic renal cell carcinoma treated with sunitinib for at least one month.

Patients are treated at the recommended United States Food and Drug Administration approved schedule of oral sunitinib administered at 25-50 mg per day for 4 weeks, in cycles of six weeks. Four weeks of treatment with sunitinib, 25-50 mg per day followed by a 2 weeks off period. In the absence of disease progression, administration of sunitinib will continue.

Within one month of the start of the study, patients will be requested to refrain from drinking grapefruit and orange juice. The study will take place in 1 sunitinib treatment cycle of 6 weeks (4 weeks of treatment with sunitinib (week 1-4) and 2 weeks off period (week 5 and 6). The grapefruit juice or orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment with sunitinib.

The first sunitinib (total drug) pharmacokinetics day will be performed after steady-state sunitinib levels are reached, meaning at least 14 days after starting sunitinib 25 - 50 mg per day treatment (week 3 in the treatment cycle of sunitinib). On this first pharmacokinetic day a dose of midazolam 7.5 mg will be given at the same time as the sunitinib dose, to observe the effect of sunitinib on CYP3A4 capacity. Before the second pharmacokinetic day (day 28 of sunitinib treatment) the patient will drink 3 times a day a glass of grapefruit juice or orange juice for three consecutive day.Patients will be assigned either to a grapefruit juice or orange juice arm. On this second pharmacokinetic day the patient again will use a dose of midazolam at the sam time as the sunitinib dose, to observe the effect of grapefruit juice or orange juice on the metabolic capacity pf CYP3A4. The third pharmacokinetic day will take place at the end of week 6 of the treatment cycle, the second week of the 2 week off period. The patient will receive a single oral dose of midazolam 7.5mg, followed by midazolam pharmacokinetics to determine the base-line CYP3A phenotypic expression. Pharmacokinetic parameters based on measurement in plasma samples will be compared between the treatment periods.

Study Timeline

• Study Start: 2007-07
• Primary Completion: 2010-12
• Study Completion: 2010-12
• Study First Submitted: 2012-11-15
• Status Verified: 2012-12
• Study First Submitted QC: 2012-12-05
• Study First Posted: 2012-12-06
• Last Update Submitted: 2012-12-18
• Last Update Posted: 2012-12-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

• Patients with imatinib-resistant gastro-intestinal stromal cell tumor or metastatic renal cell carcinoma treated with sunitinib at a dose level of 25-50 mg sunitinib per day in a 4 weeks on/2 weeks off schedule.
• Age at least 18 years
• WHO performance status < 2.
• At least 4 weeks since last chemotherapy, hormonal, or radiation therapy.
• A life expectancy of at least 12 weeks.
• Patients must have an adequate functional reserve as defined by: hemoglobin > 6.0 mmol/L, White Blood Count > 3.0 x 109/L, neutrophils > 1.5 x 109/L, platelets > 100 x 109/L, creatinine clearance > 60 mL/min, bilirubin within normal limits, Alanine transaminase and aspartate transaminase < 2.5 times the upper limit of normal (unless due to liver metastases, then < 5 times the upper limit of normal.
• Written informed consent.

Exclusion Criteria

• Patients with hematological malignancies
• Concurrent other chemotherapy, immunotherapy, or radiotherapy.
• Concurrent use of other substances known or likely to interfere with the pharmacokinetics of sunitinib (e.g., ketoconazole, cyclosporine A).
• Use of drugs, herbal preparations and/or dietary supplements known to influence the expression of CYP3A (e.g., phenytoin, rifampicin, St. John's wort, garlic supplements, milk thistle) within the preceding 2 weeks.
• Present clinical signs of symptoms of brain and/or leptomeningeal metastases confirmed by CT or MRI brain scan. A patient with brain and/or leptomeningeal metastases may be included only if he/she is asymptomatic on neurological examination and is not receiving corticosteroid therapy to control symptoms.
• Patients with uncontrolled infection.
• Concurrent severe medical problems unrelated to the malignancy that would limit full compliance with the study or expose the patient to extreme risk.
• Patients with pre-existing cardiac disease, including clinical congestive heart failure, cardiac arrhythmias requiring treatment, or a myocardial infarction within the preceding 3 months.
• Patients who have received another investigational drug within 30 days or 5 half-lives prior to entry in the study (whichever is longer).
• History of allergic reaction to compounds chemically related to sunitinib.
• Patients who are pregnant or breastfeeding.
• Patients of childbearing potential, not practicing adequate contraception.
• Patients that are unable to ingest oral medication and/or are known with gastric emptying disorders.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Grapefruit juice arm	Midazolam	The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment
Grapefruit juice arm	Grapefruit juice	The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment
Orange juice	Sunitinib	The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment.
Orange juice	Midazolam	The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment.
Orange juice	Orange juice	The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment.
Grapefruit juice arm	Sunitinib	The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment

Primary Outcome Measures

Name	Time	Method
The influence of grapefruit juice and orange juice on the steady state area under the curve (AUC) of sunitinib in cancer patients	Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)	Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. Additionally patients receive grapefruit juice on day 25-27 of treatment. To determine the influence of grapefruit juice, sunitinib pharmacokinetics (PK) will be assessed on PK day 1, which will be between treatment day 14-20 (without grapefruit juice) and on PK day 2 on day 28 of treatment (after taking grapefruit juice for 3 days).
The feasibility of midazolam as a phenotyping probe for sunitinib exposure (area under concentration time curve)in cancer patients	Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)	Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. To determine the feasibility of midazolam as a phenotyping probe, sunitinib PK from PK day 1, which is between treatment day 14-20 and the PK of midazolam from PK day 3 on day 42 of treatment (the end of the wash out period of sunitinib) will be determined.

Secondary Outcome Measures

Name	Time	Method
The effect of grapefruit juice and orange juice on CYP3A4 metabolism	Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)	Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. Additionally patients receive grapefruit juice on day 25-27 of treatment and midazolam on PK days. To determine the influence of grapefruit juice on CYP 3A4 metabolism, midazolam PK will be assessed on PK day 1, which will be between treatment day 14-20 (without grapefruit juice) and on PK day 2 on day 28 of treatment (after taking grapefruit juice for 3 days).
The influence of sunitinib on CYP3A4 activity	Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)	Subjects will receive sunitinib in the registered schedule of 4 weeks "on" (28 days) 2 weeks "off" (14 days).Sunitinib steady state is reached after 14 days. Additionally, patients receive midazolam on PK day 1 (between treatment day 14-20)and PK day 3 (day 42 of treatment,the end of the wash out period of sunitinib). To determine the influence of sunitinib on CYP3A4 activity, midazolam PK of PK day 1 (sunitinib AND midazolam) will be compared to midazolam PK of PK day 3 (midazolam alone)