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

NCT03291288 | Completed Phase 1 Results FDA Drug

• 1 other identifier: PL3397-A-U126
• Study Type: interventional
• Target: 32
• Locations: 4 countries
• Sites: 11

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.

Conditions

Drug Interaction Potential

Keywords

Tenosynovial Giant Cell Tumors (TGCT); Kit-mutant melanoma; Kit-mutant gastrointestinal stromal tumor (GIST); Cocktail drug-drug interaction (DDI)

Outcome Measures

Primary Outcomes (7)

• Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam

  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).

  Baseline to 15 days post treatment

• Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide

  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).

  Baseline to 15 days post treatment

• Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam

  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).

  Baseline to 15 days post treatment

• Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide

  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).

  Baseline to 15 days post treatment

• Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam

  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).

  Baseline to 15 days post treatment

• Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide

  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).

  Baseline to 15 days post treatment

• Overall Summary of Treatment-emergent Adverse Events

  Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.

  Baseline to 1 year post treatment

Secondary Outcomes (7)

• Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite

  Baseline to 13 days post treatment

• Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite

  Baseline to 13 days post treatment

• Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite

  Baseline to 13 days post treatment

• Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam

  Baseline to 13 days post treatment

• Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam

  Baseline to 13 days post treatment

Study Arms (1)

Pexidartinib

EXPERIMENTAL

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; Drug: Midazolam; Drug: Pexidartinib

Interventions

Tolbutamide DRUG

Commercially available tolbutamide

Also known as: Orinase

Pexidartinib

Midazolam DRUG

Commercially available midazolam

Also known as: Dormicum, Hypnovel, Versed, Others

Pexidartinib

Pexidartinib DRUG

Pexidartinib is formulated as opaque, white, 200-mg capsules

Also known as: PLX-3397

Pexidartinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Is the age of majority in country of residence
• Has a diagnosis of:
• 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)
• KIT-mutant tumor, including melanoma or gastrointestinal stromal tumor (GIST), for which there is no standard systemic therapy, or
• 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:
• intra-uterine device (nonhormonal or hormonal)
• sexual abstinence (only if this is in line with the patient's current lifestyle)
• 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

You may not qualify if:

• 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:
• safety and well-being of the participant or offspring
• safety of study staff
• analysis of results

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (11)

HonorHealth

Scottsdale, Arizona, 85258, United States

Location

University of Arizona

Tucson, Arizona, 85719, United States

Location

Stanford University

Palo Alto, California, 94304, United States

Location

University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Karmanos Cancer Center

Detroit, Michigan, 48201, United States

Location

Northwell Health

Lake Success, New York, 10042, United States

Location

Mary Crowley Cancer Research

Dallas, Texas, 75230, United States

Location

Leids Universitair Medisch Centrum

Leiden, 2333 ZA, Netherlands

Location

Christchurch Hospital NZ

Christchurch, 8011, New Zealand

Location

National Taiwan University Hospital

Taipei, 10002, Taiwan

Location

Related Publications (1)

• 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.

  PMID: 33289960 DERIVED

MeSH Terms

Conditions

Synovitis, Pigmented Villonodular

Interventions

Tolbutamide; Midazolam; Bro protein, Drosophila; pexidartinib

Condition Hierarchy (Ancestors)

Giant Cell Tumor of Tendon Sheath; Giant Cell Tumors; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Synovitis; Joint Diseases; Musculoskeletal Diseases; Tendinopathy; Muscular Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Contact for Clinical Trial Information
• Organization: Daiichi Sankyo, Inc.

CTRinfo@dsi.com

908-992-6400

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-label, single sequence study with 2 parts

Study Record Dates

• First Submitted: September 19, 2017
• First Posted: September 25, 2017
• Study Start: February 26, 2018
• Primary Completion: September 26, 2018
• Study Completion: April 16, 2021
• Last Updated: May 14, 2021
• Results First Posted: March 19, 2020

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

TW (1); NZ (1); NL (1); US (8)