Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)
Condition: Drug Interaction Potential
Intervention: Tolbutamide; Midazolam; Pexidartinib
Intervention description: Commercially available tolbutamide; Commercially available midazolam; Pexidartinib is formulated as opaque, white, 200-mg capsules
Intervention MeSH terms: Tolbutamide; Midazolam
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Intervention model description: Open-label, single sequence study with 2 parts
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Tenosynovial Giant Cell Tumors (TGCT); Kit-mutant melanoma; Kit-mutant gastrointestinal stromal tumor (GIST); Cocktail drug-drug interaction (DDI)

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.
    

Eligibility criteria:

        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