A Phase I, Open-label, Positron-Emission Tomography Study to Determine Brain Exposure of [11C]Savolitinib in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- Percentage of injected radioactivity entering the brain (%ID) as %IDmax_brain
研究概览
简要总结
The purpose of this study is to measure brain exposure of [11C]savolitinib in healthy volunteers.
This study will determine brain exposure of [11C]savolitinib in up to 8 healthy volunteers under physiological conditions, ie, when the BBB is intact. The study design allows up to 3 site visits. Two PET examinations will be performed for each healthy volunteer. The first PET examination will use IV administration of [11C]savolitinib. The second PET examination using [11C]savolitinib will occur after a single oral dose of 300 mg of savolitinib. PET image analysis will include kinetic compartment modelling using arterial input function, and will generate a set of brain exposure parameters (eg, maximum %ID, maximum [11C]savolitinib concentration in brain, partition coefficients between brain and plasma).
详细描述
This is a Phase I, open-label, non-randomised, single-centre study to determine brain distribution and exposure of [11C]savolitinib following IV bolus injections of a microdose in one cohort of healthy adult volunteers. The study is composed of the following parts:
Visit 1: Screening: Screening, including brain MRI, within 45 days prior to PET imaging
Visit 2: PET examination: Single microdose (≤ 10 μg) of [11C]savolitinib administered as an IV bolus at the start of PET imaging. Brain radioactivity measurements using PET/CT (radioactivity in brain) and radioactivity measurements in arterial blood (radioactivity in blood) will be taken over a maximum of 90 minutes. 300 mg savolitinib will be administered orally approximately 2 hours after the end of the first PET examination. The second microdose of [11C]savolitinib will be administered as IV bolus at approximately 2 hours after the oral administration of savolitinib, and a second PET examination will be conducted over 90 minutes. PET2 examination can be performed on a separate day, within 14 days after PET1, if it was not performed the same day due to technical/participant related reasons. Oral savolitinib will be given on the same day as the second PET examination.
Visit 3: Follow-up: Telephone assessment 7 days (± 3 days) after receiving the last microdose of [11C]savolitinib and PET examination
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy volunteers must be ≥ 50 to 65 years of age inclusive, at the time of signing the informed consent form and capable of giving informed consent.
- •Body weight within 50.0 - 100.0 kg and body mass index within the range 18.0 - 30.0 kg/m2 (inclusive).
- •Male or female with contraceptive use.
- •a. Male volunteers: (i) does not wish to father any children in the 6 months after the study follow-up visit and must use condoms and spermicide with sexual partners who are pregnant or who could become pregnant from the time of dosing until 6 months after savolitinib administration.
- •b. Female volunteers: Only females not of childbearing potential will be considered for enrollment in the study.
排除标准
- •Having known or suspected systemic infection (eg, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, tuberculosis), including previous or on-going infectious or autoimmune disease.
- •Current evidence of SARS-CoV-2 infection with some exceptions applied on a case by case basis.
- •Positive urine screen for drugs of abuse at screening visit, or known history of drug or alcohol abuse within the past year.
- •Any factors that may increase the risk of QTcF prolongation such as congenital of familiar long QT syndrome, chronic hypokalemia not correctable with supplements etc.
- •Any clinically significant abnormalities on 12-lead ECG, as judged by the investigator.
- •Central nervous system infarction, infection or focal lesions of clinical significance on MRI scans.
- •Brain MRI abnormalities that would interfere with image analysis, as determined by the PI
- •Presence of significant abnormalities in the medical history or physical examination or laboratory tests at screening that may interfere with the study or present a safety risk.
- •Current significant major or unstable respiratory, heart, cerebrovascular, haematological, hepatic, renal, gastrointestinal diseases, or other major disease.
- •Any concomitant medications known to be associated with Torsades de Pointes, potent inducers of cytochrome P450 3A4 (CYP3A4), strong inhibitor of CYP1A2, inhibitors or inducers of P-gp.
- •Participation in a research PET or PET/CT study in the previous 12 months, and as per the judgement of the PI participation in this study will not expose the volunteer to radiation in excess of internationally accepted limit.
- •History of autoimmune disease, severe/ongoing allergy or atopy, or history of hypersensitivity to drugs with a similar chemical structure or class to [11C]savolitinib/savolitinib or the excipients of [11C]savolitinib/savolitinib.
研究组 & 干预措施
Healthy Volunteers
Healthy volunteers will undergo two PET examinations and will receive 2 single IV doses of [11C]savolitinib (total ≤ 20 µg) and radioactivity of 400 ± 10% mBq/70 kg/per PET-CT examination, with total radiation exposure during the study of 3.86 mSv. Healthy volunteers will receive a single 300 mg dose of oral savolitinib approximately 2 hours after the end of the first PET examination and approximately 2 hours before the second IV dose of [11C]savolitinib. The second PET examination can be performed on a separate day, within 14 days after the first PET examination. Oral savolitinib will be given on the same day as the second PET examination.
干预措施: [11C]savolitinib (Drug)
Healthy Volunteers
Healthy volunteers will undergo two PET examinations and will receive 2 single IV doses of [11C]savolitinib (total ≤ 20 µg) and radioactivity of 400 ± 10% mBq/70 kg/per PET-CT examination, with total radiation exposure during the study of 3.86 mSv. Healthy volunteers will receive a single 300 mg dose of oral savolitinib approximately 2 hours after the end of the first PET examination and approximately 2 hours before the second IV dose of [11C]savolitinib. The second PET examination can be performed on a separate day, within 14 days after the first PET examination. Oral savolitinib will be given on the same day as the second PET examination.
干预措施: Savolitinib (Drug)
结局指标
主要结局
Percentage of injected radioactivity entering the brain (%ID) as %IDmax_brain
时间窗: 0-90 minutes post IV dose of [11C]savolitinib
Determine brain exposure of \[11C\]savolitinib following single, IV administration of a microdose in healthy adult volunteers
次要结局
- The following endpoint: Tmax brain(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoints: AUCbrain 0-90(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoint: VT(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoint: Cmax_brain SUV(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoint: AUCplasma 0-90(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoint: Kp(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoints: VT(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoints: Kp(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoint: AUCbrain 0-90(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoint: Kp,uu(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoints: AUCplasma 0-90(0-90 minutes post IV dose of [11C]savolitinib)
- The following endpoints: Kp,uu(0-90 minutes post IV dose of [11C]savolitinib)