A Phase 1, Single-center, Open-label, Sequential Dose-Escalation Study of ACP-196 in Healthy Subjects to Evaluate Safety, Pharmacokinetics, Pharmacodynamics, Food Effects, and Drug-Drug Interactions
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 59
- 试验地点
- 1
- 主要终点
- Maximum Observed Plasma Concentration (Cmax) of ACP-196 in Parts 1, 2, and 3
研究概览
简要总结
This study is to evaluate the safety, pharmacokinetics/pharmacodynamics (PK/PD), food-effect, and drug-drug interaction study of ACP-196 in healthy participants.
详细描述
The study is divided into 3 parts. Part 1 will include 5 cohorts (Cohorts [C] 1 to 5) and participants will receive oral ACP-196 2.5 to 50 mg twice daily (BID) and 100 mg once daily (QD) on Day 1. In Part 2 (Cohort 6), participants will receive a single oral dose of 75.0 mg QD in a fasting and a fed state, with a 7-day washout period between the 2 doses. In Part 3 (Cohort 7), participants will receive a single oral dose of 50.0 mg QD alone on Day 1 and in combination with itraconazole on Day 9. Itraconazole 200 mg will be given twice daily (12 hours apart) with meals on Days 4 to 8 and once on Day 9 with ACP-196 under a fasting state in the morning.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Body mass index (BMI) >=18.0 and <=30.0 kg/m^
- •Healthy as determined by medical history and physical examination.
- •Nonsmoker
- •Normal clinical laboratory test results and ECG, or results with minor deviations which are not considered to be clinically significant in the judgment of the investigator.
- •Men of and women of childbearing potential to follow protocol defined contraception methods.
- •Women must have negative urine pregnancy test.
- •Willingness and ability to swallow study drug capsules.
排除标准
- •Prior or ongoing clinically significant illness, medical condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
- •Evidence of ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections).
- •Women cannot be pregnant or breast feeding.
- •Significant history of drug or alcohol abuse or addiction within 3 years before study screening or as evidenced by continuing medical complications of prior drug or alcohol use.
- •History of blood or plasma donation within 90 days before first study drug administration.
- •Currently drinking over 21 units/week of ethanol
- •Drug toxicology screen positive for any prohibited drugs, illicit substances, or alcohol.
- •Anticipated need for alcohol, tobacco, or any drug during the study drug administration and immediate follow-up periods.
- •Relative to admission has any of the following exposures: has taken a prescription systemic medication within 14 days; has used an over-the counter systemic medication (other than acetaminophen) within 7 days; has ingested calcium supplements or calcium-containing vitamins within 7 days; has ingested grapefruit, grapefruit juice, or grapefruit-containing products within 7 days; has consumed alcohol within 48 hours; has taken acetaminophen within 24 hours.
- •Positive test for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis B core antibody, or hepatitis C antibody.
- •Unwillingness to avoid vigorous physical activity during inpatient clinic confinements.
- •Part 2 only - Inability or unwillingness to eat all of the ingredients of the high-fat, high-calorie meal as specified in the protocol.
- •Part 3 only - Known allergy to itraconazole or other azole compounds.
研究组 & 干预措施
Part 1 Cohort 1
Participants will receive ACP-196 2.5 mg capsule orally BID on Day 1.
干预措施: ACP-196 (Drug)
Part 1 Cohort 2
Participants will receive ACP-196 5 mg (2 x 2.5 mg capsules) orally BID on Day 1.
干预措施: ACP-196 (Drug)
Part 1 Cohort 3
Participants will receive ACP-196 25 mg capsule orally BID on Day 1.
干预措施: ACP-196 (Drug)
Part 1 Cohort 4
Participants will receive ACP-196 50 mg (2 x 25 mg capsules) orally BID on Day 1.
干预措施: ACP-196 (Drug)
Part 1 Cohort 5
Participants will receive ACP-196 100 mg (4 x 25 mg capsules) orally QD on Day 1.
干预措施: ACP-196 (Drug)
Part 2 Cohort 6
Participants will receive ACP-196 75 mg (3 x 25 mg capsules) orally QD on Day 1 and Day 8.
干预措施: ACP-196 (Drug)
Part 3 Cohort 7
Participants will receive ACP-196 50 mg (2 x 25 mg capsules) orally QD on Day 1, itraconazole 200 mg capsules BID from Days 4 to 8 with meals and then ACP-196 50 mg (2 x 25 mg capsules) along with itraconazole 200 mg capsule QD on Day 9 under fasting state.
干预措施: ACP-196 (Drug)
Part 3 Cohort 7
Participants will receive ACP-196 50 mg (2 x 25 mg capsules) orally QD on Day 1, itraconazole 200 mg capsules BID from Days 4 to 8 with meals and then ACP-196 50 mg (2 x 25 mg capsules) along with itraconazole 200 mg capsule QD on Day 9 under fasting state.
干预措施: Itraconazole (Drug)
结局指标
主要结局
Maximum Observed Plasma Concentration (Cmax) of ACP-196 in Parts 1, 2, and 3
时间窗: Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Incidences of Abnormal Clinical Laboratory Parameters Reported as TEAEs
时间窗: Part 1: From Day 1 to Day 2; Part 2 and Part 3: From Day 1 to Day 10
Incidences of Abnormal Electrocardiograms (ECGs) Reported as TEAEs
时间窗: Part 1: Day 1 ( from 1 hr predose through 1 hr postdose); Part 2: From Day 1 (1 hr predose) through Day 8 (1 hr postdose); Part 3: From Day 1 (1 hr predose) through Day 9 (1 hr postdose)
Time to reach Cmax (Tmax) of ACP-196 in Parts 1, 2, and 3
时间窗: Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Time Delay Between the Time of Dosing and the First Measurable Concentration (tlag) of ACP-196 in Parts 1, 2, and 3
时间窗: Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Incidences of Abnormal Vital Signs Reported as TEAEs
时间窗: Part 1: Day 1 ( from 1 hr predose through 1 hr postdose); Part 2: From Day 1 (1 hr predose) through Day 8 (1 hr postdose); Part 3: From Day 1 (1 hr predose) through Day 9 (1 hr postdose)
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of ACP-196 in Parts 1, 2, and 3
时间窗: Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Terminal-elimination Half-life (T1/2) of ACP-196 in Parts 1, 2, and 3
时间窗: Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Incidences of Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
时间窗: Part 1: Day 1 through Day 3; Part 2 and Part 3: Day 1 through Day 10
Area Under the Concentration-time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of ACP-196 in Parts 1, 2, and 3
时间窗: Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
Terminal-elimination Rate Constant (λz) of ACP-196 in Parts 1, 2, and 3
时间窗: Part 1: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24, 36, 48, 60h; Parts 2 and 3: predose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72h; and till 48h on Day 8 of Part 2; and till 24h on Day 9 of Part 3
次要结局
- Effect of ACP-196 on Biologic Markers of B-cell Function(1, 3, 12, 15, and 24 hrs after first dose on Day 1)
- Occupancy of Bruton's Tyrosine Kinase (BTK) by ACP-196 in Peripheral Blood Mononuclear Cells (PBMCs)(1, 3, 12, 15, and 24 hrs after first dose on Day 1)