A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor), Rifampicin (a CYP3A4 Inducer), and Omeprazole (a Proton Pump Inhibitor) on the Pharmacokinetics of a Single Oral Dose of Adavosertib in Patients With Advanced Solid Tumours
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- AstraZeneca
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Ratios of geometric means of AUCinf (Area under plasma concentration-time curve from time zero to infinity) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone
研究概览
简要总结
This is a Phase 1, open-label, non-randomised, 3-arm (A, B, and C), drug-drug interaction study in patients with advanced solid tumours.
详细描述
The study will include 3 arms consisting of a screening period of up to 28 days (Day -28 to Day -1), an intervention period (12 days for arm A, 17 days for arm B, and 12 days for arm C), and a follow-up end of treatment [EOT] visit (within 3 days after a 4-day washout period relative to the last dose of adavosertib).
Arm A of this study follows a non-randomised, open-label, 2-intervention design. Patients will receive the following 2 study interventions: a single oral dose of adavosertib alone, and a single oral dose of adavosertib administered concomitantly with itraconazole.
Arm B of this study follows a non-randomised, open-label, 2-intervention design. Patients will receive the following 2 study interventions: a single oral dose of adavosertib alone, and a single oral dose of adavosertib administered concomitantly with rifampicin.
Arm C of this study follows a non-randomised, open-label, 2-intervention design. Patients will receive the following 2 study interventions: a single oral dose of adavosertib alone, and a single oral dose of adavosertib administered concomitantly with omeprazole.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically documented, locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable.
- •Eastern Cooperative Oncology Group performance status score of 0 or
- •Predicted life expectancy ≥ 12 weeks.
- •Patients must have normal organ and marrow function at baseline, within 7 days prior to study drug administration.
- •Males and females of childbearing potential who agree to use contraceptive measures must be consistent with clinical study protocol.
排除标准
- •Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade > 2) caused by previous anticancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.
- •Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of adavosertib, itraconazole, rifampicin, and omeprazole.
- •Any significant cardiac diseases currently or within the last 6 months such as: (a) unstable angina pectoris (b) acute myocardial infarction, congestive heart failure (c) conduction abnormality not controlled with pacemaker or medication (d) significant ventricular or supraventricular arrhythmias.
- •Any of the following:
- •History or current evidence of congenital long QT syndrome;
- •concomitant medications known to prolong QT interval or history of medicationrelated QT prolongation.
- •Known to have tested positive for human immunodeficiency virus or active tuberculosis infection.
- •Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening.
- •Any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant, active infections, and active bleeding diseases) which prohibit participating in the study.
- •Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.
- •Receipt of live virus and live bacterial vaccines whilst the patient is receiving the study intervention and during the 30-day follow-up period. Inactivated flu vaccines are permitted.
- •Use of an anti-cancer treatment drug ≤ 21 days (≤ 6 weeks for nitroureas or mitomycin C) or use of an investigational product within 5 half-lives prior to the first dose of adavosertib.
- •Patient uses drugs that are sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or are moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks or 5 halflives (whichever is longer) prior to Day 1 of dosing.
- •Patients with a known hypersensitivity to adavosertib, itraconazole, rifampicin, and omeprazole or any of the excipients of the product.
- •Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
研究组 & 干预措施
Arm A
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with itraconazole.
干预措施: Adavosertib (Drug)
Arm A
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with itraconazole.
干预措施: Itraconazole (Drug)
Arm B
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with rifampicin.
干预措施: Adavosertib (Drug)
Arm B
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with rifampicin.
干预措施: Rifampicin (Drug)
Arm C
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with omeprazole.
干预措施: Adavosertib (Drug)
Arm C
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with omeprazole.
干预措施: Omeprazole (Drug)
结局指标
主要结局
Ratios of geometric means of AUCinf (Area under plasma concentration-time curve from time zero to infinity) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone
时间窗: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Assessment of the effect of itraconazole (arm A)/rifampicin (arm B)/omeprazole (arm C) on the AUCinf of adavosertib following oral dosing in patients with advanced solid tumours.
Ratios of geometric means of AUClast (Area under the plasma concentration-time curve from zero to time of last quantifiable concentration) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone
时间窗: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Assessment of the effect of itraconazole (arm A)/rifampicin (arm B)/omeprazole (arm C) on the AUClast of adavosertib following oral dosing in patients with advanced solid tumours.
Ratios of geometric means of Cmax (maximum observed plasma concentration) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone
时间窗: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Assessment of the effect of itraconazole (arm A)/rifampicin (arm B)/omeprazole (arm C) on the Cmax of adavosertib following oral dosing in patients with advanced solid tumours.
次要结局
- Descriptive statistics of t½λz (Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve)(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of Vss/F (Volume of distribution (apparent) at steady state following extravascular administration)(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of AUClast(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of λz (Terminal elimination rate constant)(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of Ctrough (Observed lowest drug concentration reached before the next dose is administered)(Arm A: Days 9-11; Arm B: Days 14-17; Arm C: Day 9)
- Summary of Adavosertib plasma concentrations with time(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of Cmax(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of AUCinf(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of tmax (Time to reach maximum observed concentration following drug administration)(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Descriptive statistics of CL/F (Apparent total body clearance of drug from plasma after extravascular administration)(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)
- Number of patients with serious and non-serious adverse events(From screening to end of study [within 30 (±7) days of last adavosertib dose])
- Descriptive statistics of Vz/F (Apparent volume of distribution during the terminal phase after extravascular administration)(Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12)