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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03291288

Enrollment

Registered

2017-09-25

Start date

2018-02-26

Completion date

2021-04-16

Last updated

2021-05-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Drug Interaction Potential

Keywords

Tenosynovial Giant Cell Tumors (TGCT), Kit-mutant melanoma, Kit-mutant gastrointestinal stromal tumor (GIST), Cocktail drug-drug interaction (DDI)

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.

Interventions

DRUGTolbutamide

Commercially available tolbutamide

DRUGMidazolam

Commercially available midazolam

DRUGPexidartinib

Pexidartinib is formulated as opaque, white, 200-mg capsules

Study design

Allocation

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Open-label, single sequence study with 2 parts

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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: 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: 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: 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: 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: 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

Measure	Time frame	Description
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.

Countries

Netherlands, New Zealand, Taiwan, United States

Participant flow

Recruitment details

A total of 32 participants who met all inclusion and no exclusion criteria were enrolled in the study; 2 participants did not receive pexidartinib treatment.

Pre-assignment details

This open-label, single sequence crossover study comprised of 2 parts. Part 1 was the initial single sequence crossover part to evaluate the effect of pexidartinib on the pharmacokinetics of midazolam and tolbutamide, the drug-drug interaction (DDI) phase. Part 2 was an evaluation of efficacy and safety of pexidartinib treatment in various tumors.

Participants by arm

Arm	Count
All Participants All participants who received pexidartinib in Part 1 and Part 2 of the study.	30
Total	30

Withdrawals & dropouts

Period	Reason	FG000	FG001
Drug-drug Interaction Phase	Adverse Event	2	0
Drug-drug Interaction Phase	Disease progression	1	0
Drug-drug Interaction Phase	Other	3	0
Pexidartinib Only	Ongoing	0	2

Baseline characteristics

Characteristic	All Participants
Age, Categorical <=18 years	2 Participants
Age, Categorical >=65 years	9 Participants
Age, Categorical Between 18 and 65 years	19 Participants
Age, Continuous	50.8 years STANDARD_DEVIATION 19.3
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	5 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) White	23 Participants
Sex: Female, Male Female	15 Participants
Sex: Female, Male Male	15 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 30	0 / 25
other Total, other adverse events	24 / 30	23 / 25
serious Total, serious adverse events	5 / 30	5 / 25

Outcome results

Primary

Overall Summary of Treatment-emergent Adverse Events

Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.

Time frame: Baseline to 1 year post treatment

Population: Treatment-emergent adverse events (TEAEs) were assessed in the Safety Analysis population.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Part 1: Midazolam Only	Overall Summary of Treatment-emergent Adverse Events	TEAEs	24 Participants
Part 1: Midazolam Only	Overall Summary of Treatment-emergent Adverse Events	Pexidartinib-related TEAEs	16 Participants
Part 1: Midazolam Only	Overall Summary of Treatment-emergent Adverse Events	Treatment-emergent serious adverse events (SAEs)	5 Participants
Part 1: Midazolam Only	Overall Summary of Treatment-emergent Adverse Events	Pexidartinib-related SAEs	1 Participants
Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Overall Summary of Treatment-emergent Adverse Events	Pexidartinib-related SAEs	1 Participants
Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Overall Summary of Treatment-emergent Adverse Events	TEAEs	23 Participants
Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Overall Summary of Treatment-emergent Adverse Events	Treatment-emergent serious adverse events (SAEs)	5 Participants
Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Overall Summary of Treatment-emergent Adverse Events	Pexidartinib-related TEAEs	20 Participants

Primary