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

NCT01743300 | Completed Phase 1 DMC

• 1 other identifier: P07.111
• Study Type: interventional
• Target: 15
• Locations: 0 countries
• Sites: N/A

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

Conditions

Healthy

Keywords

sunitinib; pharmacokinetics; phenotyping; interaction

Outcome Measures

Primary Outcomes (2)

• The influence of grapefruit juice and orange juice on the steady state area under the curve (AUC) of sunitinib in cancer patients

  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).

  Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)

• The feasibility of midazolam as a phenotyping probe for sunitinib exposure (area under concentration time curve)in cancer patients

  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.

  Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)

Secondary Outcomes (2)

• 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)

• 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)

Study Arms (2)

Grapefruit juice arm

ACTIVE COMPARATOR

The grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment

Drug: Sunitinib; Drug: Midazolam; Other: Grapefruit juice

Orange juice

ACTIVE COMPARATOR

The orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment.

Drug: Sunitinib; Drug: Midazolam; Other: Orange juice

Interventions

Sunitinib DRUG

All patients receive once daily 50 mg sunitinib for 6 weeks in the registered schedule of 4 weeks on two weeks off treatment.

Also known as: sutent

Grapefruit juice arm; Orange juice

Midazolam DRUG

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.

Also known as: Dormicum

Grapefruit juice arm; Orange juice

Orange juice OTHER

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

Orange juice

Grapefruit juice OTHER

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

Grapefruit juice arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Leiden University Medical Center: lead

MeSH Terms

Interventions

Sunitinib; Midazolam

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzodiazepines; Benzazepines

Study Officials

• Hans Gelderblom

  LUMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: November 15, 2012
• First Posted: December 6, 2012
• Study Start: July 1, 2007
• Primary Completion: December 1, 2010
• Study Completion: December 1, 2010
• Last Updated: December 19, 2012

Record last verified: 2012-12