The Influence of Genotype/Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib (Sutent, SU011248) in Patient With Imatinib Resistant Gastrointestinal Stromal Cell Tumor (GIST) or Metastatic Renal Cell Carcinoma
18 Years
N/A
Both
Healthy
Trial Information
The Influence of Genotype/Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib (Sutent, SU011248) in Patient With Imatinib Resistant Gastrointestinal Stromal Cell Tumor (GIST) or Metastatic Renal Cell Carcinoma
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.
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.
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label
Outcome Measure:
The influence of grapefruit juice and orange juice on the steady state area under the curve (AUC) of sunitinib in cancer patients
Outcome 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).
Outcome Time Frame:
Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)
Safety Issue:
No
Principal Investigator
Hans Gelderblom
Investigator Role:
Principal Investigator
Investigator Affiliation:
LUMC
Authority:
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Study ID:
P07.111
NCT ID:
NCT01743300
Start Date:
July 2007
Completion Date:
December 2010
Related Keywords:
- Healthy
- sunitinib
- pharmacokinetics
- phenotyping
- interaction
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