An Open-Label, Non-randomised, Parallel Group, Multicentre, Phase I Study to Assess the Safety and Effect of Olaparib at Steady State on the Pharmacokinetics of the Anti-hormonal Agents Anastrozole, Letrozole and Tamoxifen at Steady State, and the Effect of the Anti-hormonal Agents on Olaparib, Following Administration in Patients With Advanced Solid Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 79
- 试验地点
- 1
- 主要终点
- Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ
研究概览
简要总结
This is an open-label 2-part Phase I study in patients with advanced solid tumours. Part A of the study (mandatory) will assess the effect of olaparib on the pharmacokinetics (PK) of anastrozole, letrozole and tamoxifen and vice versa; Part B will allow patients (if eligible) continued access to olaparib after the PK phase and will provide additional safety data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 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
- •Provision of written informed consent prior to any study specific procedures
- •Male or female aged ≥18 years
- •Histological or cytological confirmation of any malignant solid tumour in an advanced or metastatic setting who meet one of the criteria below:
- •Patients should be resistant or refractory to standard treatment if such treatment exists OR
- •Patients for which no suitable effective standard therapy exists OR
- •Patients with advanced breast cancer for whom anastrozole, letrozole or tamoxifen are indicated may also enter the study (postmenopausal breast cancer patients will be eligible for any of the cohorts; however, premenopausal breast cancer patients will be eligible for the tamoxifen cohort only).
- •Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
- •Haemoglobin (Hb) ≥10.0 g/dL with no blood transfusions in the past 28 days
- •Absolute neutrophil count (ANC) ≥1.5 x 109/L
- •Platelet count ≥100 x 109/L
- •Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) (except in the case of Gilbert's disease)
- •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 x institutional ULN unless liver metastases are present, in which case they must be ≤5x ULN
- •Serum creatinine ≤1.5 x institutional ULN
- •Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
- •Patients must have a life expectancy ≥16 weeks
- •Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1 of Part A.
- •Postmenopausal is defined as:
- •Age ≥ 60 years
- •Age <60 years and amenorrheic for 1 year or more in the absence of chemotherapy and/or hormonal treatment
- •Luteinising hormone (LH), follicle stimulating hormone (FSH) and plasma oestradiol levels in the postmenopausal range for women under 60 years
- •Radiation-induced oophorectomy with last menses >1 year ago
- •Or surgical sterilisation (bilateral oophorectomy or hysterectomy)
- •Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment, and scheduled visits and examinations
- •Patients must be on stable concomitant medication regimen (with the exception of electrolyte supplements), defined as no change in medication or dose within 2 weeks prior to start of study treatment.
排除标准
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents, and/or staff at the study site)
- •Previous enrolment in the present study
- •Exposure to an investigational product (IP) (including PARP inhibitor) within 30 days or 5 half lives (whichever is the longer) prior to enrolment
- •Prior chemotherapy within 3 weeks of study entry
- •Prior radiotherapy within 2 weeks of study entry
- •If prior endocrine treatment is given, adequate washout period is required: at least 2 weeks for anastrozole, at least 4 weeks for letrozole and at least 10 weeks for tamoxifen
- •Resting ECG with QTc >470 msec detected on 2 or more time points within a 24 hour period, or family history of long QT syndrome. If ECG demonstrates QTc >470 msec, patient will be eligible only if repeat ECG demonstrates QTc <470 msec.
- •Patients who are receiving inhibitors or inducers of CYP3A4 unless washed out prior to start of study treatment.
- •Persistent toxicities (Common Toxicity Criteria for Adverse Events [CTCAE] grade ≥2) caused by previous cancer therapy, excluding alopecia and/or CTCAE grade 2 peripheral neuropathy
- •Patients with myelodysplastic syndrome/acute myeloid leukaemia
- •Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery
- •Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled seizures or active uncontrolled infection.
- •Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with absorption of the study medication
- •Patients who have gastric, gastro-oesophageal, or oesophageal cancer
- •Pregnant or breastfeeding women
- •Patients with known active Hepatitis B or C, or human immunodeficiency virus (HIV).
- •Patients with a known hypersensitivity to olaparib (all cohorts), tamoxifen (Cohort 1) anastrozole (Cohort 2), letrozole (Cohort 3), or any of the excipients of these products.
研究组 & 干预措施
Cohort 2 - Anastrozole
Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
干预措施: Olaparib (Drug)
Cohort 1 - Tamoxifen
Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
干预措施: Olaparib (Drug)
Cohort 1 - Tamoxifen
Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
干预措施: Tamoxifen (Drug)
Cohort 1 - Tamoxifen
Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.
干预措施: Pharmacokinetic sampling (Procedure)
Cohort 2 - Anastrozole
Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
干预措施: Anastrozole (Drug)
Cohort 2 - Anastrozole
Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.
干预措施: Pharmacokinetic sampling (Procedure)
Cohort 3 - Letrozole
Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
干预措施: Olaparib (Drug)
Cohort 3 - Letrozole
Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
干预措施: Letrozole (Drug)
Cohort 3 - Letrozole
Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.
干预措施: Pharmacokinetic sampling (Procedure)
结局指标
主要结局
Effect of Tamoxifen on Exposure to Olaparib - AUC0-τ
时间窗: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 31
Olaparib AUC0-τ, in the presence and absence of co-administered tamoxifen, and associated AUC0-τ treatment ratios
Effect of Olaparib on Exposure to Tamoxifen - Cmax ss
时间窗: Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
Tamoxifen, N-desmethyl tamoxifen (N-DMT) and endoxifen Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios
Effect of Tamoxifen on Exposure to Olaparib - Cmax ss
时间窗: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 31
Olaparib Cmax ss in the presence and absence of co-administered tamoxifen, and associated Cmax ss treatment ratios
Effect of Olaparib on Exposure to Anastrozole - Cmax ss
时间窗: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
Anastrozole maximum plasma concentration at steady state (Cmax ss) in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios
Effect of Anastrozole on Exposure to Olaparib - Cmax ss
时间窗: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 24
Olaparib Cmax ss in the presence and absence of co-administered anastrozole, and associated Cmax ss treatment ratios
Effect of Olaparib on Exposure to Letrozole - Cmax ss
时间窗: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
Letrozole Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios
Effect of Letrozole on Exposure to Olaparib - Cmax ss
时间窗: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 43
Olaparib Cmax ss in the presence and absence of co-administered letrozole, and associated Cmax ss treatment ratios
Effect of Olaparib on Exposure to Tamoxifen - AUC0-τ
时间窗: Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31
Tamoxifen, N-DMT and endoxifen AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios
Effect of Olaparib on Exposure to Anastrozole - AUC0-τ
时间窗: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 19 and Day 24
Anastrozole Area under plasma concentration-time curve over the dosing interval at steady state (AUC0-τ), in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios
Effect of Anastrozole on Exposure to Olaparib - AUC0-τ
时间窗: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 24
Olaparib AUC0-τ, in the presence and absence of co-administered anastrozole, and associated AUC0-τ treatment ratios
Effect of Olaparib on Exposure to Letrozole - AUC0-τ
时间窗: Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose on Day 38 and Day 43
Letrozole AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios
Effect of Letrozole on Exposure to Olaparib - AUC0-τ
时间窗: Pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post morning dose on Day 5 and Day 43
Olaparib AUC0-τ, in the presence and absence of co-administered letrozole, and associated AUC0-τ treatment ratios
次要结局
未报告次要终点