A Phase I, Open-label Study to Assess the Absolute Bioavailability of Saruparib (AZD5305) and Absorption, Distribution, Metabolism, and Excretion (ADME) of [14C]-Saruparib ([14C]-AZD5305) in Patients With Advanced Solid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- PK parameters characterized by tmax
研究概览
简要总结
This Phase I, open-label study aims to study to absolute bioavailability of Saruparib (AZD5305) and the absorption, distribution, metabolism and excretion (ADME) of [14C]-Saruparib in patients with advanced solid malignancies.
This will be done on an inpatient basis in 2 parts (single-dose oral administration with radiolabeled microtracer in Part A, single-dose IV radiolabeled administration in Part B) during which samples will be obtained of plasma, urine, feces and vomitus (where applicable).
详细描述
This is an open-label, 2-part study in participants with advanced solid malignancies and will be conducted at multiple study sites.
Participants will be assessed for study eligibility prior to admission to the study site during a 28-day screening period. Participants will take part in both Parts A and B of the study.
Part A will assess the absolute bioavailability and evaluate the PK parameters of oral Saruparib and a radiolabelled IV microdose of [14C]-Saruparib
Participants will be admitted to the study site pre-dose of Part A and will remain resident at the study site for PK sampling and safety assessments.
A washout period will be observed between doses of Saruparib in Parts A and B.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
盲法说明
No masking
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
- •Male or female ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place), at the time of signing the ICF.
- •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.
- •ECOG performance status of 0 or 1 with no deterioration over the 2 weeks prior to dosing.
- •Predicted life expectancy ≥ 12 weeks.
- •Adequate organ and marrow function as defined in the protocol
- •Willingness and ability to comply with study and follow-up procedures.
- •Able and willing to stay in hospital for specified residential periods following administration of Saruparib/[14C]-Saruparib
- •Regular bowel movements
- •Body weight within normal range specified in protocol
- •Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies Reproduction
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol
排除标准
- •Participants with a history of MDS/AML or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML is not required.
- •Participants with any known predisposition to bleeding
- •Any history of persisting severe cytopenia due to any cause
- •Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of Saruparib.
- •History of another primary malignancy, with some exceptions
- •Persistent toxicities (CTCAE Grade ≥ 2), excluding alopecia, caused by previous anticancer therapy.
- •Spinal cord compression or brain metastases for at least 4 weeks prior to start of study intervention unless asymptomatic and stable
- •Abnormal cardiac function exclusions or cardiovascular disease
- •History of arrhythmia
- •Active HBV (positive HBsAg result) or HCV.
- •Evidence of active and uncontrolled HIV infection.
- •Active tuberculosis infection
- •Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
- •As judged by the investigator, any other evidence of diseases (such as severe or uncontrolled systemic diseases or active uncontrolled infections which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or would jeopardise compliance with the protocol.
- •Any prior treatment with a PARP inhibitor or platinum chemotherapy.
- •Other anticancer therapy (chemotherapy, immunotherapy, hormonal anticancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agent is not permitted until the last PK sampling is completed.
- •Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention
- •Concomitant use of medications or herbal supplements known to be CYP3A4 strong and moderate inhibitors or inducers
- •Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes
- •Participants who have participated in another absorption, distribution, metabolism, and excretion study within 1 year prior to screening.
- •Participation in another clinical study with a study intervention administered in the last 3 months or 5 half-lives prior to dosing, whichever is longer.
- •Participants with a known hypersensitivity to Saruparib or any of the excipients of the product.
- •Participants who have been administered any amount of a [14C]-labelled compound within the last 12 months.
- •Use of tobacco- or nicotine-containing products or alcohol may be exclusionary
- •Poor peripheral venous access (venous access via a port will be permitted).
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- •Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
- •Previous enrolment in the present study.
- •For female participants only: currently pregnant (confirmed with positive pregnancy test) or planning to become pregnant, breast-feeding, or intending to donate/retrieve ova before 6 months after the last dose of Saruparib.
研究组 & 干预措施
Primary Treatment Arm - AZD5305
Part A will assess absolute bioavailability via oral administration of Saruparib (AZD5305) and IV [14C]-saruparib microtracer.
Part B will assess ADME via IV [14C]-saruparib administration
干预措施: [14C]-AZD5305 microtracer (Drug)
Primary Treatment Arm - AZD5305
Part A will assess absolute bioavailability via oral administration of Saruparib (AZD5305) and IV [14C]-saruparib microtracer.
Part B will assess ADME via IV [14C]-saruparib administration
干预措施: Saruparib (AZD5305) (Drug)
Primary Treatment Arm - AZD5305
Part A will assess absolute bioavailability via oral administration of Saruparib (AZD5305) and IV [14C]-saruparib microtracer.
Part B will assess ADME via IV [14C]-saruparib administration
干预措施: [14C]-AZD5305 (therapeutic dose) (Drug)
结局指标
主要结局
PK parameters characterized by tmax
时间窗: Day 4
tmax
PK parameters characterized by t1/2(lambda)z
时间窗: Day 4
t1/2(lambda)z
Pharmacokinetics of Saruparib(Part B)
时间窗: Day 8
AUCinf
Absolute bioavailability (F) of Saruparib
时间窗: Day 4
Absolute bioavailability (F) of Saruparib
Total radioactivity recovery in urine and faeces
时间窗: Day 8
Total radioactivity recovery in urine and faeces
PK parameters characterized by AUCinf
时间窗: Day 4
AUCinf
Ratio of AUCinf of plasma Saruparib relative to AUCinf of metabolite
时间窗: Day 4
Ratio of AUCinf of plasma Saruparib relative to AUCinf of metabolite
Mass balance parameters as characterized by amount excreted and cumulative amount excreted in urine, faeces and total (urine and faeces combined)
时间窗: Day 8
Cumulative amount excreted in urine, faeces and total (urine and faeces combined)
Amount excreted and cumulative amount excreted in urine, faeces and total (urine and faeces combined) expressed as a percentage of the administered dose
时间窗: Day 8
Amount excreted and cumulative amount excreted in urine, faeces and total (urine and faeces combined) expressed as a percentage of the administered dose.
PK parameters characterized by AUClast
时间窗: Day 4
AUClast
PK parameters characterized by Cmax
时间窗: Day 4
Cmax
次要结局
- Metabolic profiling of a single oral dose of [14C]-Saruparib (Part B)(Day 8)
- Characterize the safety of Saruparib in participants with advanced solid malignancies by incidence and severity of AEs, laboratory abnormalities, 12-lead ECG abnormalities, vital signs abnormalities, physical examination findings(Day 14)