HealthyPhase 1NCT01743300
The Influence of Phenotype, Grapefruit Juice and Orange Juice on the Pharmacokinetics of Sunitinib in Cancer Patients
A Phase 1 study testing Sunitinib, Midazolam and Orange juice in people with Healthy, run by Leiden University Medical Center.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Healthy
- What is being tested?
- Sunitinib, Midazolam and Orange juice
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- No sites listed yet
- Study dates
- Jul 2007to Dec 2010
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
About this study
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
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
Read the 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.
- Conditions
- Healthy
- Keywords
- sunitinib, pharmacokinetics, phenotyping, interaction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SunitinibDrug
Also called sutent
All patients receive once daily 50 mg sunitinib for 6 weeks in the registered schedule of 4 weeks on two weeks off treatment.
MidazolamDrug
Also called Dormicum
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.
Orange juiceOther
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
Grapefruit juiceOther
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
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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. Receives: Drug: Sunitinib; Drug: Midazolam; Other: Orange juice |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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.
Measured: 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
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).
Measured: 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
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)
Measured: Patients will be included for 42 days into the study. Within these 42 days, 3 PK measuring days are planned (see also description)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Dec 2012 (estimated)
- Study startJul 2007
- Primary completionDec 2010
- Study completionDec 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Hans Gelderblom, Leiden University Medical Center
- Investigators
- Hans Gelderblom, Principal investigator, LUMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01743300
- Sponsor's protocol ID
- P07.111
- Status last verified
- Dec 2012
- First submitted
- 15 Nov 2012
- Last updated
- 19 Dec 2012
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01743300
- Acronym / sponsor ID
- P07.111
- Conditions
- Healthy
- Keywords
- sunitinib, pharmacokinetics, phenotyping, interaction
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Study start
- Jul 2007
- Primary completion
- Dec 2010 (actual)
- Study completion
- Dec 2010 (actual)
- First posted
- 6 Dec 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Grapefruit juice arm | Active comparator | Drug: Sunitinib, Drug: Midazolam, Other: Grapefruit juiceThe grapefruit juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment |
| Orange juice | Active comparator | Drug: Sunitinib, Drug: Midazolam, Other: Orange juiceThe orange juice will be administered 3 times per day for 1 period of 3 days in the 4th week of treatment. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SunitinibAlso: sutentAll patients receive once daily 50 mg sunitinib for 6 weeks in the registered schedule of 4 weeks on two weeks off treatment. | Drug | Grapefruit juice arm, Orange juice |
| MidazolamAlso: DormicumAll 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. | Drug | Grapefruit juice arm, Orange juice |
| Orange juiceThe 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 | Other | Orange juice |
| Grapefruit juiceThe 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 | Other | Grapefruit juice arm |
Primary outcome
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)
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)
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.
2 secondary outcomes
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)
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2012.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hans Gelderblom principal investigator
LUMC
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Sunitinib, Midazolam and Orange juice in people with Healthy, run by Leiden University Medical Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2012. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2012.