Clinical trial NCT03291288: Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug Interaction Potential
Keywords: Tenosynovial Giant Cell Tumors (TGCT)
Kit-mutant melanoma
Kit-mutant gastrointestinal stromal tumor (GIST)
Cocktail drug-drug interaction (DDI)
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2017-09-25
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Open-label, single sequence study with 2 parts
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam
timeFrame: Baseline to 15 days post treatment
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide
timeFrame: Baseline to 15 days post treatment
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam
timeFrame: Baseline to 15 days post treatment
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide
timeFrame: Baseline to 15 days post treatment
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam
timeFrame: Baseline to 15 days post treatment
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide
timeFrame: Baseline to 15 days post treatment
measure: Overall Summary of Treatment-emergent Adverse Events
timeFrame: Baseline to 1 year post treatment
Secondary outcomes:
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite
timeFrame: Baseline to 13 days post treatment
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite
timeFrame: Baseline to 13 days post treatment
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite
timeFrame: Baseline to 13 days post treatment
measure: Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
timeFrame: Baseline to 13 days post treatment
measure: Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam
timeFrame: Baseline to 13 days post treatment
measure: Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam
timeFrame: Baseline to 13 days post treatment
measure: Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam
timeFrame: Baseline to 13 days post treatment
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Lake Success
country: United States
facility: Northwell Health
state: New York
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Christchurch
country: New Zealand
facility: Christchurch Hospital NZ
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_CHAIR
References:
citation: Lewis JH, Gelderblom H, van de Sande M, Stacchiotti S, Healey JH, Tap WD, Wagner AJ, Pousa AL, Druta M, Lin CC, Baba HA, Choi Y, Wang Q, Shuster DE, Bauer S. Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors. Oncologist. 2021 May;26(5):e863-e873. doi: 10.1002/onco.13629. Epub 2020 Dec 24.