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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 11
- 主要终点
- Overall Summary of Treatment-emergent Adverse Events
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Tolbutamide (Drug)
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.
干预措施: Midazolam (Drug)
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.
干预措施: Pexidartinib (Drug)
结局指标
主要结局
Overall Summary of Treatment-emergent Adverse Events
时间窗: 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.
Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam
时间窗: 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).
Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam
时间窗: 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).
Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide
时间窗: 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).
Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam
时间窗: 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).
Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide
时间窗: 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).
Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide
时间窗: 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).
次要结局
- 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)
- Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam(Baseline to 13 days post treatment)
- Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam(Baseline to 13 days post treatment)