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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hans Gelderblom, Leiden University Medical Center
ClinicalTrials.gov Identifier:
NCT01743300
First received: November 15, 2012
Last updated: December 18, 2012
Last verified: December 2012
  Purpose

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

Condition Intervention Phase
Healthy
Drug: Sunitinib
Drug: Midazolam
Other: Orange juice
Other: Grapefruit juice
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Leiden University Medical Center:

Primary Outcome Measures:
  • The influence of grapefruit juice and orange juice on the steady state area under the curve (AUC) of sunitinib in cancer patients [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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:
  • The effect of grapefruit juice and orange juice on CYP3A4 metabolism [ 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) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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)


Enrollment: 15
Study Start Date: July 2007
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Grapefruit juice arm
The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment
Drug: Sunitinib
All patients receive once daily 50 mg sunitinib for 6 weeks in the registered schedule of 4 weeks on two weeks off treatment.
Other Name: sutent
Drug: Midazolam
All patients receive three times midazolam 7,5 mg on PK day 1,2, and 3 e.g. between day 14-21 of treatment, on day 28 of treatment and on day 42 of treatment.
Other Name: Dormicum
Other: Grapefruit juice
The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment with sunitinib, just before PK day 2 on day 28 of treatment
Active Comparator: Orange juice
The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment.
Drug: Sunitinib
All patients receive once daily 50 mg sunitinib for 6 weeks in the registered schedule of 4 weeks on two weeks off treatment.
Other Name: sutent
Drug: Midazolam
All patients receive three times midazolam 7,5 mg on PK day 1,2, and 3 e.g. between day 14-21 of treatment, on day 28 of treatment and on day 42 of treatment.
Other Name: Dormicum
Other: Orange juice
The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment with sunitinib, just before PK day 2 on day 28 of treatment

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01743300

Sponsors and Collaborators
Leiden University Medical Center
Investigators
Principal Investigator: Hans Gelderblom LUMC
  More Information

No publications provided

Responsible Party: Hans Gelderblom, Prof., Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT01743300     History of Changes
Other Study ID Numbers: P07.111
Study First Received: November 15, 2012
Last Updated: December 18, 2012
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Leiden University Medical Center:
sunitinib
pharmacokinetics
phenotyping
interaction

Additional relevant MeSH terms:
Midazolam
Sunitinib
Adjuvants, Anesthesia
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on August 27, 2014