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Completed

NCT Number: NCT03291288

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

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.

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Key information

Conditions

Drug Interaction Potential Giant Cell Tumor of Tendon Sheath Giant Cell Tumors Joint Diseases Muscular Diseases Musculoskeletal Diseases Neoplasms Neoplasms by Histologic Type Neoplasms, Connective Tissue Neoplasms, Connective and Soft Tissue Synovitis Synovitis, Pigmented Villonodular Tendinopathy

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Leids Universitair Medisch Centrum, Leiden, Netherlands

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

tolbutamide

Drug

Commercially available tolbutamide

Other names: Orinase

midazolam

Drug

Commercially available midazolam

Other names: Dormicum, Hypnovel, Versed, Others

Pexidartinib

Drug

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

Other names: PLX-3397

Primary outcomes

  1. Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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 outcomes

  1. Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Daiichi Sankyo

Industry

Registry information

Official study 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

Important dates

Study start
2018
Primary completion
2018
Study completion
2021
First posted
Sep 25, 2017
Registry last updated
May 14, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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