Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)

Phase 1

Completed

Conditions: Drug Interaction Potential

Interventions: Drug: Tolbutamide
Drug: Midazolam
Drug: Pexidartinib

Registration Number: NCT03291288

Lead Sponsor: Daiichi Sankyo

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Is the age of majority in country of residence
Has a diagnosis of:
1. 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)
2. KIT-mutant tumor, including melanoma or gastrointestinal stromal tumor (GIST), for which there is no standard systemic therapy, or
3. 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:
1. intra-uterine device (nonhormonal or hormonal)
2. sexual abstinence (only if this is in line with the patient's current lifestyle)
3. 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:
1. safety and well-being of the participant or offspring
2. safety of study staff
3. analysis of results

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Pexidartinib	Tolbutamide	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.
Pexidartinib	Midazolam	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.
Pexidartinib	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.

Primary Outcome Measures

Name	Time	Method
Overall Summary of Treatment-emergent Adverse Events	Baseline to 1 year post treatment	Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.
Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam	Baseline to 15 days post treatment	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).
Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam	Baseline to 15 days post treatment	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).
Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide	Baseline to 15 days post treatment	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).
Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam	Baseline to 15 days post treatment	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).
Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide	Baseline to 15 days post treatment	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).
Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide	Baseline to 15 days post treatment	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).

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite	Baseline to 13 days post treatment	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.
Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite	Baseline to 13 days post treatment	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.
Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite	Baseline to 13 days post treatment	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.
Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam	Baseline to 13 days post treatment	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.
Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam	Baseline to 13 days post treatment	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.
Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam	Baseline to 13 days post treatment	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.
Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam	Baseline to 13 days post treatment	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.

Trial Locations

Locations (11): University of Kansas Cancer Center
🇺🇸
Westwood, Kansas, United States
University of Arizona
🇺🇸
Tucson, Arizona, United States
HonorHealth
🇺🇸
Scottsdale, Arizona, United States
Mary Crowley Cancer Research
🇺🇸
Dallas, Texas, United States
Stanford University
🇺🇸
Palo Alto, California, United States
Christchurch Hospital NZ
🇳🇿
Christchurch, New Zealand
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Northwell Health
🇺🇸
Lake Success, New York, United States
Karmanos Cancer Center
🇺🇸
Detroit, Michigan, United States
Leids Universitair Medisch Centrum
🇳🇱
Leiden, Netherlands