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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03291288
Recruitment Status : Active, not recruiting
First Posted : September 25, 2017
Results First Posted : March 19, 2020
Last Update Posted : September 24, 2020
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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
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
Actual Primary Completion Date : September 26, 2018
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: Pexidartinib

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.

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




Primary Outcome Measures :
  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 Outcome Measures :
  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.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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
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United States, Arizona
HonorHealth
Scottsdale, Arizona, United States, 85258
University of Arizona
Tucson, Arizona, United States, 85719
United States, California
Stanford University
Palo Alto, California, United States, 94304
United States, Kansas
University of Kansas Cancer Center
Westwood, Kansas, United States, 66205
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Karmanos Cancer Center
Detroit, Michigan, United States, 48201
United States, New York
Northwell Health
Lake Success, New York, United States, 10042
United States, Texas
Mary Crowley Cancer Research
Dallas, Texas, United States, 75230
Netherlands
Leids Universitair Medisch Centrum
Leiden, Netherlands, 2333 ZA
New Zealand
Christchurch Hospital NZ
Christchurch, New Zealand, 8011
Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 10002
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Investigators
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Study Chair: Global Clinical Leader Daiichi Sankyo, Inc.
  Study Documents (Full-Text)

Documents provided by Daiichi Sankyo, Inc.:
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT03291288    
Other Study ID Numbers: PL3397-A-U126
First Posted: September 25, 2017    Key Record Dates
Results First Posted: March 19, 2020
Last Update Posted: September 24, 2020
Last Verified: September 2020
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 https://vivli.org/. 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://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all 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, the European Union and/or Japan 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://vivli.org/ourmember/daiichi-sankyo/

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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:
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Tolbutamide
Midazolam
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