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

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ClinicalTrials.gov Identifier: NCT03291288
Recruitment Status : Active, not recruiting
First Posted : September 25, 2017
Results First Posted : March 19, 2020
Last Update Posted : September 24, 2020
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Study Type Interventional
Study Design Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Drug Interaction Potential
Interventions Drug: Tolbutamide
Drug: Midazolam
Drug: Pexidartinib
Enrollment 32
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.
Arm/Group Title Part 1: Drug-drug Interaction Phase Part 2: Pexidartinib Only
Hide 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
Ongoing 1 0
Completed 25 0
Not Completed 7 0
Reason Not Completed
Adverse Event             3             0
Disease progression             2             0
Did not receive treatment             2             0
Period Title: Pexidartinib Only
Started 0 [1] 25 [2]
Completed 0 0
Not Completed 0 25
Reason Not Completed
Adverse Event             0             1
Disease progression             0             8
Patient request             0             1
Other             0             2
Ongoing             0             13
[1]
This is a crossover trial; participants who completed Part 1 continued to Part 2.
[2]
1 participant completed Part 1 but did not enter Part 2.
Arm/Group Title All Participants
Hide Arm/Group Description All participants who received pexidartinib in Part 1 and Part 2 of the study.
Overall Number of Baseline Participants 30
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
<=18 years
2
   6.7%
Between 18 and 65 years
19
  63.3%
>=65 years
9
  30.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants
50.8  (19.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
Female
15
  50.0%
Male
15
  50.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
American Indian or Alaska Native
0
   0.0%
Asian
5
  16.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
23
  76.7%
More than one race
0
   0.0%
Unknown or Not Reported
2
   6.7%
1.Primary Outcome
Title Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Mean (Standard Deviation)
Unit of Measure: ng/mL
44400  (13100) 46700  (16300) 44400  (12200)
3.Primary Outcome
Title Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Median (Full Range)
Unit of Measure: hours
0.525
(0.333 to 1.37)
0.5
(0.417 to 1.42)
0.5
(0.333 to 0.917)
4.Primary Outcome
Title Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Median (Full Range)
Unit of Measure: hours
2.90
(1 to 8.2)
2.94
(1.52 to 8.08)
3.17
(2.45 to 6.02)
5.Primary Outcome
Title Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Mean (Standard Deviation)
Unit of Measure: ng*hour/mL
500000  (196000) 585000  (234000) 700000  (207000)
7.Primary Outcome
Title Overall Summary of Treatment-emergent Adverse Events
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 30 25
Measure Type: Count of Participants
Unit of Measure: Participants
TEAEs
24
  80.0%
23
  92.0%
Pexidartinib-related TEAEs
16
  53.3%
20
  80.0%
Treatment-emergent serious adverse events (SAEs)
5
  16.7%
5
  20.0%
Pexidartinib-related SAEs
1
   3.3%
1
   4.0%
8.Secondary Outcome
Title Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 30 25
Mean (Standard Deviation)
Unit of Measure: ng/mL
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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 30 25
Median (Full Range)
Unit of Measure: hours
Pexidartinib
2.03
(1.08 to 7.83)
1.93
(0.92 to 8.03)
ZAAD-1006a
6.04
(2.37 to 9.07)
2.53
(0 to 8.25)
10.Secondary Outcome
Title Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 30 25
Mean (Standard Deviation)
Unit of Measure: ng*hour/mL
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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Median (Full Range)
Unit of Measure: hours
1.0
(0.333 to 1.45)
0.933
(0.417 to 1.37)
0.833
(0.383 to 1.55)
13.Secondary Outcome
Title Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Mean (Standard Deviation)
Unit of Measure: ng*hour/mL
200  (93) 206  (95.5) 212  (99.6)
14.Secondary Outcome
Title Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 32 30 25
Mean (Standard Deviation)
Unit of Measure: Ratio
587  (359) 750  (391) 1220  (657)
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
Hide 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 (%) Affected / at Risk (%)
Total   1/30 (3.33%)   0/25 (0.00%) 
Hide Serious Adverse Events
Part 1: Drug-drug Interaction Phase Part 2: Pexidartinib Only
Affected / at Risk (%) Affected / at Risk (%)
Total   5/30 (16.67%)   5/25 (20.00%) 
Cardiac disorders     
Pericardial effusion  1  0/30 (0.00%)  1/25 (4.00%) 
Cardiac tamponade  1  0/30 (0.00%)  1/25 (4.00%) 
Gastrointestinal disorders     
Malignant bowel obstruction  1  1/30 (3.33%)  0/25 (0.00%) 
Dysphagia  1  1/30 (3.33%)  0/25 (0.00%) 
Oesophagitis  1  0/30 (0.00%)  1/25 (4.00%) 
Large intestinal obstruction  1  1/30 (3.33%)  0/25 (0.00%) 
Gastrointestinal haemorrhage  1  0/30 (0.00%)  1/25 (4.00%) 
Hepatobiliary disorders     
Cholestasis  1  0/30 (0.00%)  1/25 (4.00%) 
Immune system disorders     
Hypersensitivity  1  1/30 (3.33%)  0/25 (0.00%) 
Pneumonia  1  0/30 (0.00%)  1/25 (4.00%) 
Injury, poisoning and procedural complications     
Subdural haematoma  1  0/30 (0.00%)  1/25 (4.00%) 
Musculoskeletal and connective tissue disorders     
Chest wall haematoma  1  0/30 (0.00%)  1/25 (4.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant pleural effusion  1  0/30 (0.00%)  1/25 (4.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  1/30 (3.33%)  0/25 (0.00%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Part 1: Drug-drug Interaction Phase Part 2: Pexidartinib Only
Affected / at Risk (%) Affected / at Risk (%)
Total   24/30 (80.00%)   23/25 (92.00%) 
Blood and lymphatic system disorders     
Anemia  1  5/30 (16.67%)  4/25 (16.00%) 
Eye disorders     
Eye swelling  1  0/30 (0.00%)  2/25 (8.00%) 
Gastrointestinal disorders     
Nausea  1  3/30 (10.00%)  3/25 (12.00%) 
Diarrhea  1  4/30 (13.33%)  0/25 (0.00%) 
Dysphagia  1  2/30 (6.67%)  1/25 (4.00%) 
Abdominal pain  1  0/30 (0.00%)  3/25 (12.00%) 
Vomiting  1  2/30 (6.67%)  4/25 (16.00%) 
Gastrointestinal haemorrhage  1  0/30 (0.00%)  2/25 (8.00%) 
Constipation  1  1/30 (3.33%)  3/25 (12.00%) 
General disorders     
Chills  1  2/30 (6.67%)  1/25 (4.00%) 
Fatigue  1  4/30 (13.33%)  7/25 (28.00%) 
Investigations     
Alanine aminotransferase increased  1  3/30 (10.00%)  2/25 (8.00%) 
White blood cell count decreased  1  1/30 (3.33%)  6/25 (24.00%) 
Neutrophil count decreased  1  0/30 (0.00%)  4/25 (16.00%) 
Gamma-glutamyltransferase increased  1  2/30 (6.67%)  1/25 (4.00%) 
Blood lactate dehydrogenase increased  1  2/30 (6.67%)  0/25 (0.00%) 
Blood cholesterol increased  1  1/30 (3.33%)  2/25 (8.00%) 
Aspartate aminotransferase increased  1  5/30 (16.67%)  1/25 (4.00%) 
Metabolism and nutrition disorders     
Hyponatraemia  1  1/30 (3.33%)  2/25 (8.00%) 
Hypophosphataemia  1  1/30 (3.33%)  4/25 (16.00%) 
Decreased appetite  1  2/30 (6.67%)  4/25 (16.00%) 
Musculoskeletal and connective tissue disorders     
Muscle spasms  1  0/30 (0.00%)  2/25 (8.00%) 
Arthralgia  1  4/30 (13.33%)  0/25 (0.00%) 
Nervous system disorders     
Headache  1  2/30 (6.67%)  1/25 (4.00%) 
Dysgeusia  1  3/30 (10.00%)  3/25 (12.00%) 
Dizziness  1  1/30 (3.33%)  2/25 (8.00%) 
Respiratory, thoracic and mediastinal disorders     
Productive cough  1  2/30 (6.67%)  0/25 (0.00%) 
Cough  1  2/30 (6.67%)  1/25 (4.00%) 
Skin and subcutaneous tissue disorders     
Hair colour changes  1  0/30 (0.00%)  10/25 (40.00%) 
Pruritus  1  4/30 (13.33%)  0/25 (0.00%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Contact for Clinical Trial Information
Organization: Daiichi Sankyo, Inc.
Phone: 908-992-6400
EMail: CTRinfo@dsi.com
Layout table for additonal information
Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT03291288    
Other Study ID Numbers: PL3397-A-U126
First Submitted: September 19, 2017
First Posted: September 25, 2017
Results First Submitted: February 12, 2020
Results First Posted: March 19, 2020
Last Update Posted: September 24, 2020