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

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03291288
• Collaborator: (none)
• Enrollment: 32
• Locations: 11
• Arm: 1
• Actual Duration (Months): 37.6
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Drug Interaction Potential	Drug: Tolbutamide; Drug: Midazolam; Drug: Pexidartinib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open-label, single sequence study with 2 partsOpen-label, single sequence study with 2 parts
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Feb 26, 2018
• Actual Primary Completion Date: Sep 26, 2018
• Actual Study Completion Date: Apr 16, 2021

Arms and Interventions

Arm

Intervention/Treatment

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.

Drug: Tolbutamide; Commercially available tolbutamide; Other Names: Orinase ; Drug: Midazolam; Commercially available midazolam; Other Names: Dormicum Hypnovel Versed Others ; Drug: Pexidartinib; Pexidartinib is formulated as opaque, white, 200-mg capsules; Other Names: PLX-3397

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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).

3. 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).

4. 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).

5. 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).

6. 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).

7. 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.

Secondary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth	Scottsdale	Arizona	United States	85258
2	University of Arizona	Tucson	Arizona	United States	85719
3	Stanford University	Palo Alto	California	United States	94304
4	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
5	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	Karmanos Cancer Center	Detroit	Michigan	United States	48201
7	Northwell Health	Lake Success	New York	United States	10042
8	Mary Crowley Cancer Research	Dallas	Texas	United States	75230
9	Leids Universitair Medisch Centrum	Leiden		Netherlands	2333 ZA
10	Christchurch Hospital NZ	Christchurch		New Zealand	8011
11	National Taiwan University Hospital	Taipei		Taiwan	10002

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

• Study Chair: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 28, 2017

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT03291288
• Other Study ID Numbers: PL3397-A-U126
• First Posted: Sep 25, 2017
• Last Update Posted: May 14, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daiichi Sankyo, Inc.: Tenosynovial Giant Cell Tumors (TGCT); Kit-mutant melanoma; Kit-mutant gastrointestinal stromal tumor (GIST); Cocktail drug-drug interaction (DDI)
• Additional relevant MeSH terms: Tolbutamide; Midazolam

Study Results

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 Detail	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.

Arm/Group Title	Part 1: Drug-drug Interaction Phase	Part 2: Pexidartinib Only
Arm/Group Description	On Day 1, participants received the single oral dose of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/day) administered as 400 mg twice daily (BID) was initiated and continued 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) was co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning dose of pexidartinib (400 mg).	All participants received pexidartinib twice daily (BID) dosing in 28-day cycles at the 400 mg/day dose for up to one year.
Period Title: Drug-drug Interaction Phase
STARTED	32	0
COMPLETED	26	0
NOT COMPLETED	6	0
Period Title: Drug-drug Interaction Phase
STARTED	0	26
COMPLETED	0	24
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants who received pexidartinib in Part 1 and Part 2 of the study.
Overall Participants	30
Age (Count of Participants)
<=18 years	2 6.7%
Between 18 and 65 years	19 63.3%
>=65 years	9 30%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.8 (19.3)
Sex: Female, Male (Count of Participants)
Female	15 50%
Male	15 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 16.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	23 76.7%
More than one race	0 0%
Unknown or Not Reported	2 6.7%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam
Description	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).
Time Frame	Baseline to 15 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Midazolam Only	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of midazolam (2 mg) on Day 1.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Mean (Standard Deviation) [ng/mL]	13.6 (6.8)	12.0 (4.9)	9.7 (4.1)

2. Primary Outcome

Title	Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide
Description	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).
Time Frame	Baseline to 15 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Tolbutamide Only	Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 1)	Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of tolbutamide (500 mg) on Day 1.	All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Mean (Standard Deviation) [ng/mL]	44400 (13100)	46700 (16300)	44400 (12200)

3. Primary Outcome

Title	Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam
Description	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).
Time Frame	Baseline to 15 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Midazolam Only	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of midazolam (2 mg) on Day 1.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Median (Full Range) [hours]	0.525	0.5	0.5

4. Primary Outcome

Title	Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide
Description	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).
Time Frame	Baseline to 15 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Tolbutamide Only	Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 1)	Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of tolbutamide (500 mg) on Day 1.	All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Median (Full Range) [hours]	2.90	2.94	3.17

5. Primary Outcome

Title	Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam
Description	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).
Time Frame	Baseline to 15 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Midazolam Only	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of midazolam (2 mg) on Day 1.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Mean (Standard Deviation) [ng*hour/mL]	43.7 (34.1)	31.6 (19.6)	18.5 (8.2)

6. Primary Outcome

Title	Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide
Description	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).
Time Frame	Baseline to 15 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Tolbutamide Only	Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 1)	Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of tolbutamide (500 mg) on Day 1.	All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Mean (Standard Deviation) [ng*hour/mL]	500000 (196000)	585000 (234000)	700000 (207000)

7. Primary Outcome

Title	Overall Summary of Treatment-emergent Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Part 1: Drug-drug Interaction Phase	Part 2: Pexidartinib Only
Arm/Group Description	On Day 1, participants received the single oral dose of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/day) administered as 400 mg twice daily (BID) was initiated and continued 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) was co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning dose of pexidartinib (400 mg).	All participants received pexidartinib twice daily (BID) dosing in 28-day cycles at the 400 mg/day dose for up to one year.
Measure Participants	30	25
TEAEs	24 80%	23 NaN
Pexidartinib-related TEAEs	16 53.3%	20 NaN
Treatment-emergent serious adverse events (SAEs)	5 16.7%	5 NaN
Pexidartinib-related SAEs	1 3.3%	1 NaN

8. Secondary Outcome

Title	Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite
Description	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.
Time Frame	Baseline to 13 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Pexidartinib (Cycle 1, Day 1)	Part 1: Pexidartinib (Cycle 1, Day 11)
Arm/Group Description	Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.	Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.
Measure Participants	30	25
Pexidartinib	3140 (1250)	8320 (2530)
ZAAD-1006a	3330 (1520)	13500 (5980)

9. Secondary Outcome

Title	Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite
Description	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.
Time Frame	Baseline to 13 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Pexidartinib (Cycle 1, Day 1)	Part 1: Pexidartinib (Cycle 1, Day 11)
Arm/Group Description	Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.	Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.
Measure Participants	30	25
Pexidartinib	2.03	1.93
ZAAD-1006a	6.04	2.53

10. Secondary Outcome

Title	Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite
Description	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.
Time Frame	Baseline to 13 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Pexidartinib (Cycle 1, Day 1)	Part 1: Pexidartinib (Cycle 1, Day 11)
Arm/Group Description	Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.	Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.
Measure Participants	30	25
Pexidartinib	14400 (5870)	53200 (17800)
ZAAD-1006a	18300 (7240)	102000 (44100)

11. Secondary Outcome

Title	Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
Description	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.
Time Frame	Baseline to 13 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Midazolam Only	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of midazolam (2 mg) on Day 1.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Mean (Standard Deviation) [ng/mL]	49.7 (17.9)	52.1 (17.4)	55.7 (17.4)

12. Secondary Outcome

Title	Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
Description	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.
Time Frame	Baseline to 13 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Midazolam Only	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of midazolam (2 mg) on Day 1.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Median (Full Range) [hours]	1.0	0.933	0.833

13. Secondary Outcome

Title	Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam
Description	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.
Time Frame	Baseline to 13 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Midazolam Only	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of midazolam (2 mg) on Day 1.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Mean (Standard Deviation) [ng*hour/mL]	200 (93)	206 (95.5)	212 (99.6)

14. Secondary Outcome

Title	Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam
Description	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.
Time Frame	Baseline to 13 days post treatment

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Arm/Group Title	Part 1: Midazolam Only	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)	Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)
Arm/Group Description	All participants received a single oral dose of midazolam (2 mg) on Day 1.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.	All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.
Measure Participants	32	30	25
Mean (Standard Deviation) [Ratio]	587 (359)	750 (391)	1220 (657)

Adverse Events

Time Frame	Adverse events were collected after first dose up to 28 days after the last dose of study drug, up to 1 year.
Adverse Event Reporting Description	A treatment emergent adverse event (TEAE) was defined as an adverse event that emerges during treatment of Pexidartinib, having been absent pretreatment (Pexidartinib), or worsens relative to the pre-treatment (Pexidartinib) state.
Arm/Group Title	Part 1: Drug-drug Interaction Phase		Part 2: Pexidartinib Only
Arm/Group Description	On Day 1, participants received the single oral dose of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/day) administered as 400 mg twice daily (BID) was initiated and continued 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) was co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning dose of pexidartinib (400 mg).		All participants received pexidartinib twice daily (BID) dosing in 28-day cycles at the 400 mg/day dose for up to one year.
All Cause Mortality
	Part 1: Drug-drug Interaction Phase		Part 2: Pexidartinib Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		0/25 (0%)
Serious Adverse Events
	Part 1: Drug-drug Interaction Phase		Part 2: Pexidartinib Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/30 (16.7%)		5/25 (20%)
Cardiac disorders
Pericardial effusion	0/30 (0%)		1/25 (4%)
Cardiac tamponade	0/30 (0%)		1/25 (4%)
Gastrointestinal disorders
Malignant bowel obstruction	1/30 (3.3%)		0/25 (0%)
Dysphagia	1/30 (3.3%)		0/25 (0%)
Oesophagitis	0/30 (0%)		1/25 (4%)
Large intestinal obstruction	1/30 (3.3%)		0/25 (0%)
Gastrointestinal haemorrhage	0/30 (0%)		1/25 (4%)
Hepatobiliary disorders
Cholestasis	0/30 (0%)		1/25 (4%)
Immune system disorders
Hypersensitivity	1/30 (3.3%)		0/25 (0%)
Pneumonia	0/30 (0%)		1/25 (4%)
Injury, poisoning and procedural complications
Subdural haematoma	0/30 (0%)		1/25 (4%)
Musculoskeletal and connective tissue disorders
Chest wall haematoma	0/30 (0%)		1/25 (4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion	0/30 (0%)		1/25 (4%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/30 (3.3%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: Drug-drug Interaction Phase		Part 2: Pexidartinib Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/30 (80%)		23/25 (92%)
Blood and lymphatic system disorders
Anemia	5/30 (16.7%)		4/25 (16%)
Eye disorders
Eye swelling	0/30 (0%)		2/25 (8%)
Gastrointestinal disorders
Nausea	3/30 (10%)		3/25 (12%)
Diarrhea	4/30 (13.3%)		0/25 (0%)
Dysphagia	2/30 (6.7%)		1/25 (4%)
Abdominal pain	0/30 (0%)		3/25 (12%)
Vomiting	2/30 (6.7%)		4/25 (16%)
Gastrointestinal haemorrhage	0/30 (0%)		2/25 (8%)
Constipation	1/30 (3.3%)		3/25 (12%)
General disorders
Chills	2/30 (6.7%)		1/25 (4%)
Fatigue	4/30 (13.3%)		7/25 (28%)
Investigations
Alanine aminotransferase increased	3/30 (10%)		2/25 (8%)
White blood cell count decreased	1/30 (3.3%)		6/25 (24%)
Neutrophil count decreased	0/30 (0%)		4/25 (16%)
Gamma-glutamyltransferase increased	2/30 (6.7%)		1/25 (4%)
Blood lactate dehydrogenase increased	2/30 (6.7%)		0/25 (0%)
Blood cholesterol increased	1/30 (3.3%)		2/25 (8%)
Aspartate aminotransferase increased	5/30 (16.7%)		1/25 (4%)
Metabolism and nutrition disorders
Hyponatraemia	1/30 (3.3%)		2/25 (8%)
Hypophosphataemia	1/30 (3.3%)		4/25 (16%)
Decreased appetite	2/30 (6.7%)		4/25 (16%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/30 (0%)		2/25 (8%)
Arthralgia	4/30 (13.3%)		0/25 (0%)
Nervous system disorders
Headache	2/30 (6.7%)		1/25 (4%)
Dysgeusia	3/30 (10%)		3/25 (12%)
Dizziness	1/30 (3.3%)		2/25 (8%)
Respiratory, thoracic and mediastinal disorders
Productive cough	2/30 (6.7%)		0/25 (0%)
Cough	2/30 (6.7%)		1/25 (4%)
Skin and subcutaneous tissue disorders
Hair colour changes	0/30 (0%)		10/25 (40%)
Pruritus	4/30 (13.3%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.