Cancer neoplasms
Conditions
Interventions
- tolbutamide reference treatment: single oral dose of tolbutamide (500 mg) on
Day 1.
- Midazolam reference treatment: single oral dose of midazolam (2 mg) on Day 1.
- tolbutamide test treatment: sin
Sponsors
Daiichi Pharmaceutical
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1.Age * 18 y or * the legal age for being considered as an adult in the country where the patient is screened at the time of signing informed consent. 2.DA histopathologically diagnosed tumor as follows: a.DTenosynovial 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. b.DKIT-mutant tumor, including melanoma or gastrointestinal stromal tumor (GIST), for which there is no standard systemic therapy. c.DOther 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. 3.DWomen of childbearing potential must have a negative serum pregnancy test within 14 d prior to enrollment. (Where demanded by local regulations, this test may be required within 72 h prior to enrollment). 4.DMen and women of childbearing potential are permitted in the study as long as they consent to avoid getting their partner pregnant or becoming pregnant, respectively, by using a highly effective contraception method, as described below, throughout the study and up to 90 d after completion. Highly effective methods of contraception include intra-uterine device (nonhormonal or hormonal); bilateral tubal occlusion; vasectomy; sexual abstinence (only if this is in line with the patient's current lifestyle); or barrier methods (eg, condom, diaphragm) used in combination with hormonal methods associated with inhibition of ovulation. Women of nonchildbearing potential may be included if they are either surgically sterile or have been postmenopausal for * 1 y. Women who have documentation of at least 12 mo of spontaneous amenorrhea and have a follicle stimulating hormone level > 40 mIU/mL will be considered postmenopausal. The cut-off for performing a follicle- stimulating hormone test is * 50 years old. 5.DAdequate hematologic, hepatic, and renal function, defined by: *DAbsolute neutrophil count * 1.5 × 109/L. *DHemoglobin > 10 g/dL. *DPlatelet count * 100 × 109/L. *DAspartate aminotransferase (AST) and alanine aminotransferase (ALT) * upper limit of normal (ULN). *DTotal bilirubin (TBil) and direct bilirubin (DBil) * ULN with an exception of patients with confirmed Gilbert's syndrome. For patients with confirmed Gilbert's syndrome, the total bilirubin should be * 1.5 × ULN. *DSerum creatinine * 1.5 × ULN. 6.DWillingness and ability to use a paper pill diary. 7.DWillingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
Exclusion criteria
Exclusion criteria: 1.Known active or chronic human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection, or positive hepatitis B (HepB) surface antigen. Prior hepatitis infection that has been treated with highly effective therapy with no evidence of residual infection and with normal liver function (ALT, AST, total and direct bilirubin * ULN) is allowed. 2.DKnown active tuberculosis. 3.DHepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic reasons. Gilbert's disease is allowed if TBil is * 1.5 × ULN. 4.Women who are breastfeeding. 5.Patients with poor metabolizer status of cytochrome P450 (CYP) 2C9. 6.Patients on potent CYP2C9, CYP3A4, and uridine 5' diphospho- glucuronosyltransferase (UDGT) family 1 member A4 (UGT1A4) inducer and inhibitors and potent P glycoprotein (P-gp) inhibitors and inducers, unless these medications are discontinued at least 14 d before study drug administration. Foods or beverages containing CYP3A4/5 inhibitors (eg, grapefruit, pomegranate, pomelo, and star fruit) should be avoided throughout the study. 7.Anti-tumor or investigational agent therapy within 4 weeks prior to Day 1. 8.A screening Fridericia-corrected QT (QTcF) interval * 450 ms (men) or * 470 ms (women). 9.History of hypersensitivity to any investigational products, including their excipients. 10.Inability to swallow oral medication. 11.Inability to complete study procedures. 12.Patients on tolbutamide or midazolam and unable to change to alternate therapy. Prior therapy with tolbutamide or midazolam is allowed with a washout period of at least 4 wk. 13.Patients with contraindications for tolbutamide or midazolam
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PK parameters of midazolam and tolbutamide: Cmax, tmax, and AUClast. If data permits, other PK parameters including t1/2 and AUCinf will be calculated. | — |
Secondary
| Measure | Time frame |
|---|---|
| PK - Plasma PK parameters (Cmax, Tmax, AUClast) will be calculated for pexidartinib and its metabolite, ZAAD-1006a - Plasma PK parameters (Cmax, Tmax, AUClast) will be calculated for midazolam metabolite, 5-hydroxy midazolam and also metabolite to parent ratio (MPR) for 5-hydroxy midazolam and midazolam will be calculated Efficacy - Best objective response per RECIST 1.1 - Duration of response - Time to progression (for TGCT and other non-malignant tumors) - Progression-free survival (for malignant tumors) Safety - TEAEs - Vital signs - Electrocardiograms (ECGs) - Clinical laboratory tests including AST/ALT/Total bilirubin (TBil) Exploratory Endpoints - PGx biomarkers - Optional: PDy biomarkers - Optional: Tumor biomarker analysis | — |
Countries
Netherlands
Outcome results
None listed