Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Digestive System Diseases

Musculoskeletal Diseases

Rare Diseases

Melanoma

Gastrointestinal Stromal Tumors

Giant Cell Tumors

Giant Cell Tumor of Tendon Sheath

Pigmented Villonodular Synovitis

Adjuvants, Anesthesia

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Hypoglycemic Agents

Midazolam

Tolbutamide

Anesthetics

Hypnotics and Sedatives

Anti-Anxiety Agents

Anesthetics, Intravenous

Anesthetics, General

GABA Modulators

Neurotransmitter Agents

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.

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

Pexidartinib

Global Clinical Leader

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.

Open-label, single sequence study with 2 parts

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

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

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/

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 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).

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

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.

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.

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.

Daiichi Sankyo

A treatment emergent adverse event (TEAE) was defined as an adverse event that emerges during treatment of Pexidartinib, having been absent pretreatment (Pexidartinib), or worsens relative to the pre-treatment (Pexidartinib) state.

On Day 1, participants received the single oral dose of midazolam (2 mg) and tolbutamide (500 mg).

On Day 3, pexidartinib (800 mg/day) administered as 400 mg twice daily (BID) was initiated and continued 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) was co-administered with the morning pexidartinib dose (400 mg).

On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) was co-administered with the morning dose of pexidartinib (400 mg).

Part 1: Drug-drug Interaction Phase

All participants received pexidartinib twice daily (BID) dosing in 28-day cycles at the 400 mg/day dose for up to one year.

Part 2: Pexidartinib Only

All participants who received pexidartinib in Part 1 and Part 2 of the study.

All Participants

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Contact for Clinical Trial Information

All participants received a single oral dose of midazolam (2 mg) on Day 1.

Part 1: Midazolam Only

All participants received a single oral dose of midazolam (2 mg) on Day 3 concomitantly with pexidartinib and on Day 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.

Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1)

Part 1: Pexidartinib + Midazolam (Cycle 1, Day 11)

Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable population.

Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam

All participants received a single oral dose of tolbutamide (500 mg) on Day 1.

Part 1: Tolbutamide Only

All participants received a single oral dose of tolbutamide (500 mg) concomitantly with pexidartinib and on Days 3 and 13 following approximately 10 days of pexidartinib twice daily (BID) dosing.

Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 1)

Part 1: Pexidartinib + Tolbutamide (Cycle 1, Day 11)

Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide

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

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

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

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

TEAEs

Pexidartinib-related TEAEs

Treatment-emergent serious adverse events (SAEs)

Pexidartinib-related SAEs

Treatment-emergent adverse events (TEAEs) were assessed in the Safety Analysis population.

Overall Summary of Treatment-emergent Adverse Events

ZAAD-1006a

Pexidartinib was administered orally as a total daily dose of 800 mg (400 mg BID) starting from Day 3.

Part 1: Pexidartinib (Cycle 1, Day 1)

Part 1: Pexidartinib (Cycle 1, Day 11)

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

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

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

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

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

Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam

Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam

Drug-drug Interaction Phase

Pexidartinib Only

Gastrointestinal Agents

Analgesics

Antitussive Agents

Respiratory System Agents

Anti-Infective Agents

Anti-Obesity Agents

Vasoconstrictor Agents

Omeprazole

Levomethorphan

Dextromethorphan

Rifampin

Ketoconazole

2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide

Gamma Secretase Inhibitors and Modulators

Antacids

Anti-Ulcer Agents

Proton Pump Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Clotrimazole

Miconazole

Antifungal Agents

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Phenylpropanolamine

Guaifenesin

Chlorpheniramine, phenylpropanolamine drug combination

Excitatory Amino Acid Antagonists

Analgesics, Opioid

Narcotics

Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.

Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only.

Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.

Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only.

Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.

Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only.

Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.

Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only.

Gamma-Secretase Inhibitor RO4929097

Midazolam Hydrochloride

Dextromethorphan Hydrobromide

Pharmacological Study

Laboratory Biomarker Analysis

George Wilding

This randomized phase I trial studies the side effects and best dose of RO4929097 in treating patients with advanced solid tumors. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To evaluate the extent that RO4929097 induces its own metabolism using a 20mg dose on Regimen I and a 50mg dose on Regimen II by comparing Cycle 1 Day 1 and Day 10 plasma pharmacokinetic parameters.

SECONDARY OBJECTIVES:

I. To evaluate the effect of the strong inhibitor of CYP3A4, ketoconazole, on RO4929097 plasma pharmacokinetics.

II. To evaluate the effect of the strong inducer of CYP3A4, 2D6 and 2C9, rifampin on RO4929097 plasma pharmacokinetics.

III. To evaluate the effect of RO4929097 on the plasma pharmacokinetics of CYP450 substrates; midazolam (CYP3A4), omeprazole (CYP2C19), tolbutamide (CYP2C9) and dextromethorphan (CYP2D6) after single dose and chronic administration.

IV. To assess the influence of polymorphisms in CYP3A4, 3A5, 2C9, ABCB1, and 2D6 on RO4929097 plasma pharmacokinetics V. To assess any evidence of clinical activity (CR, PR, SD) in patients with advanced solid tumors.

OUTLINE: Patients are randomized to 1 of 2 treatment regimens.

Regimen I (low-dose of RO4929097): Patients receive low-dose RO4929097 orally (PO) once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV over 1 minute, omeprazole PO, tolbutamide PO, and dextromethorphan hydrobromide PO on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.

Arm A: Patients receive low-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and ketoconazole PO once daily on days 1-10 for course 2 only. For course 3 and beyond, patients receive low-dose RO4929097 on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Arm B: Patients receive low-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and rifampin PO once daily on days 1-10 for course 2 only. For course 3 and beyond, patients receive low-dose RO4929097 on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Regimen II (high-dose of RO4929097): Patients receive high-dose RO4929097 PO once daily on days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to 1 of 2 treatment arms.

Arm A: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral ketoconazole once daily on days 1-10 for course 2 only.

Arm B: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral rifampin once daily on days 1-10 for course 2 only.

In all arms, treatment with RO4929097 repeats every 21 days for \>= 3 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetics studies and evaluation of SNPs in CYP2D6, CYP2C9, ABCB1, and CYP3A4/5.

After completion of study therapy, patients are followed up for 30 days.

Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced Solid Tumors

Randomized Drug Interaction Study of RO4929097 for Advanced Solid Tumors

Compared using a paired t-test. Evaluated using a non-parametric Wilcoxon Signed Rank test.

Evaluated using a non-parametric Wilcoxon Signed Rank test. Analysis of variance will be used to evaluate changes between Regimen I and Regimen II.

Measured using lease-square regression models.

National Cancer Institute (NCI)

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Three study periods and continued access to tasisulam every 28 days (except Period 1 which was tolbutamide only and lasted 4 days) until disease progression:

Period 1: 500 milligram (mg) tolbutamide administered on Day 1.

Period 2: 500 mg of tolbutamide and individualized tasisulam dose \[based on area under the curve albumin-corrected threshold (AUCalb)\]. The AUCalb is a surrogate marker for unbound tasisulam, and this dosing approach represents the maximum level of unbound tasisulam which may be achieved clinically, administered on Day 1.

Period 3: Individualized tasisulam dose (based on AUCalb) administered on Day 1 and 500 mg tolbutamide administered on Day 4.

Tasisulam

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

The purpose of this study was to assess the effect of tasisulam as an inhibitor of CYP2C9, using tolbutamide as a probe substrate. This study was to have 3 treatment periods, and continued access in an extension period. Period 1 is 4 days in length. Periods 2 and 3 are each approximately 28 days in length. Due to the early termination of the trial, only 1 Period 3 participant enrolled in the extension period before study termination.

A Drug Interaction Study of Tasisulam in Patients With Advanced Cancer or Lymphoma

The Effect of Tasisulam on the CYP2C9-Mediated Metabolism of Tolbutamide: A Pharmacokinetic Interaction Study in Cancer Patients With Advanced and/or Metastatic Solid Tumors or Lymphoma

AUC0-∞ is defined as the area under the concentration time curve from time 0 to infinity.

Eli Lilly and Company

Adverse events (AEs) that occurred during Period 1 and during Period 2 when 500 mg tolbutamide was administered orally prior to individualized intravenous dosing (based on AUCalb) of tasisulam.

AEs that occurred during Periods 2 and 3 when both 500 mg oral tolbutamide and individualized intravenous tasisulam (based on AUCalb) were administered.

Tasisulam and Tolbutamide

AEs that occurred during Period 3 Day 1 through Day 4 until just before 500 mg oral tolbutamide was administered on Day 4, 72 hours.

Three study periods: Period 1 which was tolbutamide only and lasted 4 days and Periods 2 and 3 which had continued access to tasisulam every 28 days until disease progression:

Period 1: 500 mg tolbutamide administered once on Day 1.

Period 2: 500 mg of tolbutamide and individualized tasisulam dose administered once on Day 1.

Period 3: individualized tasisulam dose administered once on Day 1 and 500 mg tolbutamide administered once on Day 4.

United Kingdom

Region of Enrollment

All participants were included in the analysis.

Chief Medical Officer

Period 2: 500 mg of tolbutamide and individualized tasisulam dose (based on AUCalb) administered once on Day 1

Period 2: Tasisulam and Tolbutamide

All enrolled participants who started Period 2 (tasisulam and tolbutamide).

Pharmacokinetics of Tolbutamide, Concurrent Dosing, Area Under the Curve (AUC 0-∞)

Period 3: Individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on Day 4.

Tasisulam and Tolbutamide: Period 3

All enrolled participants who started period 3 (tasisulam then tolbutamide).

Pharmacokinetics of Tolbutamide, Staggered Dosing in Period 3, Area Under the Curve (AUC 0-∞)

Period 1: 500 mg tolbutamide administered once on Day 1

Tolbutamide: Period 1

Period 2: 500 mg of tolbutamide and individualized tasisulam dose (based on AUCalb) administered once on Day 1.

Tasisulam and Tolbutamide: Period 2

Period 3: individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on Day 4.

All enrolled participants who started Periods 1, 2, or 3.

Pharmacokinetics of Tolbutamide, Maximum Concentration (Cmax)

Period 1: Tolbutamide

Period 2: 500 mg tolbutamide and an individualized tasisulam dose (based on AUCalb) administered once on Day 1.

Period 3: Individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on day 4 (administration day in period 3 could adjusted based on interim pharmacokinetic \[PK\] analyses)

Period 3: Tasisulam and Tolbutamide

Pharmacokinetics of Tolbutamide, Observed Time at Maximal Concentration (Tmax)

Period 1: 500 milligram (mg) tolbutamide administered once on Day 1

Period 2: 500 mg of tolbutamide and individualized tasisulam dose (based on AUCalb) administered once on Day 1

Period 3: individualized tasisulam dose (based on AUCalb) administered once on Day 1 and 500 mg tolbutamide administered once on day 4

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)	NCT03291288	Drug Interactio...	Tolbutamide Midazolam Pexidartinib	18 Years -	Daiichi Sankyo
Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced Solid Tumors	NCT01218620	Adult Solid Neo...	Gamma-Secretase... Ketoconazole Rifampin Midazolam Hydro... Omeprazole Tolbutamide Dextromethorpha... Pharmacological... Laboratory Biom...	18 Years -	National Cancer Institute (NCI)
A Drug Interaction Study of Tasisulam in Patients With Advanced Cancer or Lymphoma	NCT01185548	Lymphoma Advanced Cancer	Tolbutamide Tasisulam	18 Years -	Eli Lilly and Company

Spots Global Cancer Trial Database for tolbutamide

Every month we try and update this database with for tolbutamide cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for tolbutamide

Every month we try and update this database with for tolbutamide cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for tolbutamide cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.