- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03291288
Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)
An Open-label, Single Sequence, Crossover Drug-drug Interaction Study Assessing the Effect of Pexidartinib on the Pharmacokinetics of CYP3A4 and CYP2C9 Substrates in Patients
This study has two parts.
Part 1 will evaluate how pexidartinib affects the way the body processes CYP3A4 and CYP2C9 substrates using midazolam and tolbutamide, respectively, as probe agents.
Part 2 will test the efficacy and safety of pexidartinib treatment in various tumor types.
In Part 2, the same participants will continue to receive pexidartinib twice daily.
Participants will be allowed to continue using pexidartinib as long as the participant derives benefit.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Leiden, Netherlands, 2333 ZA
- Leids Universitair Medisch Centrum
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Christchurch, New Zealand, 8011
- Christchurch Hospital NZ
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Taipei, Taiwan, 10002
- National Taiwan University Hospital
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Arizona
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Scottsdale, Arizona, United States, 85258
- HonorHealth
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Tucson, Arizona, United States, 85719
- University of Arizona
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California
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Palo Alto, California, United States, 94304
- Stanford University
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Kansas
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Westwood, Kansas, United States, 66205
- University of Kansas Cancer Center
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Dana-Farber Cancer Institute
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Michigan
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Detroit, Michigan, United States, 48201
- Karmanos Cancer Center
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New York
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Lake Success, New York, United States, 10042
- Northwell Health
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Texas
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Dallas, Texas, United States, 75230
- Mary Crowley Cancer Research
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Is the age of majority in country of residence
Has a diagnosis of:
- tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations and for whom surgery is not an option (prior pexidartinib is permitted for TGCT patients unless ineffective or not tolerated and there has been a washout period of at least 4 weeks)
- KIT-mutant tumor, including melanoma or gastrointestinal stromal tumor (GIST), for which there is no standard systemic therapy, or
- other solid tumors (all comers) for which there is no standard systemic therapy and there is a rationale for use of pexidartinib at the Investigator's discretion
- If a female of childbearing potential, had a negative serum pregnancy test within 14 days before enrollment, or within 72 hours before enrollment where required
Is a non-sterile male or female willing to use of one of the protocol-defined highly effective contraception methods:
- intra-uterine device (nonhormonal or hormonal)
- sexual abstinence (only if this is in line with the patient's current lifestyle)
- barrier methods (eg, condom, diaphragm) used in combination with hormonal methods associated with inhibition of ovulation
- Is a surgically sterile male or female, or is postmenopausal for at least 1 year, at least 50 years of age, with a follicle-stimulating hormone level > 40 milli-International units per mL (mIU/mL)
- Has adequate hematologic, hepatic, and renal function as defined by the protocol
- Is able and willing to follow all study procedures
- Has provided a signed informed consent
Exclusion Criteria:
- Is pregnant or breastfeeding
- Is unable to swallow oral medication
- Is unable to follow study procedures
- Is taking or has taken any medications or therapies outside of protocol-defined parameters
Has any disease or condition that, per protocol or in the opinion of the investigator, might affect:
- safety and well-being of the participant or offspring
- safety of study staff
- analysis of results
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Pexidartinib
Part 1 (Drug-drug Interaction Phase): On Day 1, all participants will receive a single oral dose each of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/d) in twice daily (400 mg BID) dosing will be initiated and continue throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning dose of pexidartinib (400 mg). Part 2 (Efficacy and Safety Phase): All participants will continue to receive pexidartinib 400 mg BID. |
Commercially available tolbutamide
Other Names:
Commercially available midazolam
Other Names:
Pexidartinib is formulated as opaque, white, 200-mg capsules
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam
Time Frame: Baseline to 15 days post treatment
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Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
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Baseline to 15 days post treatment
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Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide
Time Frame: Baseline to 15 days post treatment
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Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
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Baseline to 15 days post treatment
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Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam
Time Frame: Baseline to 15 days post treatment
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Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
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Baseline to 15 days post treatment
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Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide
Time Frame: Baseline to 15 days post treatment
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Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
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Baseline to 15 days post treatment
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Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam
Time Frame: Baseline to 15 days post treatment
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Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
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Baseline to 15 days post treatment
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Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide
Time Frame: Baseline to 15 days post treatment
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Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
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Baseline to 15 days post treatment
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Overall Summary of Treatment-emergent Adverse Events
Time Frame: Baseline to 1 year post treatment
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Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.
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Baseline to 1 year post treatment
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite
Time Frame: Baseline to 13 days post treatment
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Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
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Baseline to 13 days post treatment
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Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite
Time Frame: Baseline to 13 days post treatment
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Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
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Baseline to 13 days post treatment
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Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite
Time Frame: Baseline to 13 days post treatment
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Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
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Baseline to 13 days post treatment
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Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
Time Frame: Baseline to 13 days post treatment
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Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
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Baseline to 13 days post treatment
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Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
Time Frame: Baseline to 13 days post treatment
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Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
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Baseline to 13 days post treatment
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Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam
Time Frame: Baseline to 13 days post treatment
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Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
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Baseline to 13 days post treatment
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Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam
Time Frame: Baseline to 13 days post treatment
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Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15). Plasma pharmacokinetic parameters calculated for Midazolam metabolite. 1-hydroxy midazolam and midazolam for the MPR value. |
Baseline to 13 days post treatment
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Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Global Clinical Leader, Daiichi Sankyo, Inc.
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Central Nervous System Depressants
- Anesthetics, Intravenous
- Anesthetics, General
- Anesthetics
- Tranquilizing Agents
- Psychotropic Drugs
- Hypnotics and Sedatives
- Adjuvants, Anesthesia
- Anti-Anxiety Agents
- GABA Modulators
- GABA Agents
- Midazolam
- Tolbutamide
Other Study ID Numbers
- PL3397-A-U126
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- Study Protocol
- Statistical Analysis Plan (SAP)
- Clinical Study Report (CSR)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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