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

Daiichi Sankyo

Status and phase: Completed; Phase 1

Conditions: Drug Interaction Potential

Treatments: Drug: Pexidartinib; Drug: Tolbutamide; Drug: Midazolam

Study type: Interventional

Funder types: Industry

Identifiers

NCT03291288

PL3397-A-U126

Details and patient eligibility

About

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.

Enrollment: 32 patients

Sex: All

Ages: 18+ years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Sequential Assignment

Masking: None (Open label)

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32 participants in 1 patient group

Pexidartinib

Experimental group

Description:

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.

Treatment:

Drug: Midazolam

Drug: Tolbutamide

Drug: Pexidartinib