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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 : Recruiting
First Posted : September 25, 2017
Last Update Posted : May 9, 2018
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

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.


Condition or disease Intervention/treatment Phase
Drug Interaction Potential Drug: Tolbutamide Drug: Midazolam Drug: Pexidartinib Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Open-label, single sequence study with 2 parts
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 26, 2018
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019


Arm Intervention/treatment
Active Comparator: Part 1 - Reference treatment
On Day 1 all participants will receive a single oral dose each of midazolam (2 mg) and tolbutamide (500 mg), followed by blood draws for pharmacokinetic (PK) analysis.
Drug: Tolbutamide
Commercially available tolbutamide
Other Name: Orinase
Drug: Midazolam
Commercially available midazolam
Other Names:
  • Dormicum
  • Hypnovel
  • Versed
  • Others
Experimental: Part 1 - Test Treatment 1
On Day 3 all participants will receive a single oral dose each of midazolam (2 mg) and tolbutamide (500 mg) with morning dose of pexidartinib (400 mg) followed by blood draws for PK analysis.
Drug: Tolbutamide
Commercially available tolbutamide
Other Name: Orinase
Drug: Midazolam
Commercially available midazolam
Other Names:
  • Dormicum
  • Hypnovel
  • Versed
  • Others
Drug: Pexidartinib
Pexidartinib is formulated as opaque, white, 200-mg capsules
Other Name: PLX-3397
Experimental: Part 1 - Test Treatment 2

All participants will receive only the 400 mg pm dose of pexidartinib on Day 3 and continue twice-daily (BID) dosing of pexidartinib (400 mg for the am dose, and 400 mg for the pm dose) until Day 13.

On Day 13, all participants will receive a single oral dose of midazolam (2 mg) and tolbutamide (500 mg) with the morning dose of pexidartinib (400 mg) followed by blood draws for PK analysis.

Drug: Tolbutamide
Commercially available tolbutamide
Other Name: Orinase
Drug: Midazolam
Commercially available midazolam
Other Names:
  • Dormicum
  • Hypnovel
  • Versed
  • Others
Drug: Pexidartinib
Pexidartinib is formulated as opaque, white, 200-mg capsules
Other Name: PLX-3397
Experimental: Part 2 - Pexidartinib only

On Day 13, all participants will receive a pm dose of 400 mg pexidartinib only.

All participants will continue to receive pexidartinib BID dosing in 28-day cycles at the 400 mg/day dose for up to one year. The dose of pexidartinib may be further modified within that year, depending upon tolerance as defined in the protocol.

Drug: Pexidartinib
Pexidartinib is formulated as opaque, white, 200-mg capsules
Other Name: PLX-3397



Primary Outcome Measures :
  1. Maximum concentration (Cmax) for midazolam [ Time Frame: within 15 days ]
    Plasma samples for midazolam will be 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)

  2. Cmax for tolbutamide [ Time Frame: within 15 days ]
    Plasma samples for tolbutamide will be 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. Time to maximum concentration (Tmax) for midazolam [ Time Frame: within 15 days ]
  4. Tmax for tolbutamide [ Time Frame: within 15 days ]
  5. Area under the curve to the last observable concentration (AUClast) for midazolam [ Time Frame: within 15 days ]
  6. AUClast for tolbutamide [ Time Frame: within 15 days ]
  7. Number of participants with an adverse event by the end of Part 2 [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. Overall response rate (ORR) by the end of Part 2 [ Time Frame: 1 year ]
    ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) based on locally read tumor assessments according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or other applicable assessment of treatment response based upon the applicable tumor.

  2. Cmax for pexidartinib and its metabolites [ Time Frame: within 13 days ]
    Plasma samples for pexidartinib and its metabolite will be 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. Tmax for pexidartinib and its metabolite [ Time Frame: within 13 days ]
  4. AUClast for pexidartinib and its metabolite [ Time Frame: within 13 days ]
  5. Cmax for midazolam metabolite [ Time Frame: within 13 days ]
  6. Tmax for midazolam metabolite [ Time Frame: within 13 days ]
  7. AUClast for midazolam metabolite [ Time Frame: within 13 days ]
  8. Metabolite to parent ratio (MPR) for midazolam [ Time Frame: within 13 days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03291288


Locations
United States, Arizona
HonorHealth Recruiting
Scottsdale, Arizona, United States, 85258
Contact: Site Coordinator    480-323-1348    Jeffrey.dolim@honorhealth.com   
University of Arizona Recruiting
Tucson, Arizona, United States, 85719
Contact: Site Coordinator    520-694-9082    kris7c@email.arizona.edu   
United States, California
Stanford University Not yet recruiting
Palo Alto, California, United States, 94304
Contact: Site Coordinator    650-723-2868    shmonshi@stanford.edu   
United States, Kansas
University of Kansas Cancer Center Not yet recruiting
Westwood, Kansas, United States, 66205
Contact: Site Coordinator    913-945-7551    xlam@kumc.edu   
United States, Massachusetts
Dana-Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Coordinator    617-582-7503    ssolomon1@partners.org   
United States, Michigan
Karmanos Cancer Center Recruiting
Detroit, Michigan, United States, 48201
Contact: Site Coordinator    313-576-9749    schneidk@karmanos.org   
United States, New York
Montefiore Medical Center Not yet recruiting
Bronx, New York, United States, 10461
Contact: Study Coordinator    718-405-8515    mhghalib@montefiore.org   
Northwell Health Not yet recruiting
Lake Success, New York, United States, 10042
Contact: Site Coordinator    516-734-7629    esham@northwell.edu   
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Contact: Site Coordinator    214-658-1985    nkarimi@marycrowley.org   
United States, Washington
University of Washington/ Seattle Cancer Care Alliance Withdrawn
Seattle, Washington, United States, 98109
Korea, Republic of
The Research Institute for Future Medicine Withdrawn
Seoul, Korea, Republic of, 06351
Netherlands
Leids Universitair Medisch Centrum Not yet recruiting
Leiden, Netherlands, 2333 ZA
Contact: Site Coordinator    +31 715261965    j.ouwerkerk@lumc.nl   
New Zealand
Christchurch Hospital NZ Not yet recruiting
Christchurch, New Zealand, 8011
Contact: Site Coordinator    +64 33786282    Rachel.hart@cdhb.health.nz   
Taiwan
National Taiwan University Hospital Not yet recruiting
Taipei, Taiwan, 10002
Contact: Site Coordinator    886-223123456 ext 67460    lovelyeffie@ntuh.gov.tw   
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Investigators
Study Chair: Global Clinical Leader Daiichi Sankyo, Inc.

Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT03291288     History of Changes
Other Study ID Numbers: PL3397-A-U126
First Posted: September 25, 2017    Key Record Dates
Last Update Posted: May 9, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at http://www.clinicalstudydatarequest.com. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://www.clinicalstudydatarequest.com/Study-Sponsors-DS-Details.aspx
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Studies for which the medicine and indication have received EU and US marketing approval on or after 01 January 2014 or by the US or EU Health Authorities when regulatory submissions in both regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States and the European Union from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://www.clinicalstudydatarequest.com/Study-Sponsors-DS-Details.aspx

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Daiichi Sankyo, Inc.:
Tenosynovial Giant Cell Tumors (TGCT)
Kit-mutant melanoma
Kit-mutant gastrointestinal stromal tumor (GIST)
Cocktail drug-drug interaction (DDI)

Additional relevant MeSH terms:
Midazolam
Tolbutamide
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents