Pharmacokinetic Boosting of Olaparib to Improve Exposure, Tolerance and Cost-effectiveness
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 10
- 主要终点
- Part B: Progression-free survival (PFS)
研究概览
简要总结
Olaparib is a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor, originally used for the maintenance treatment of women with platinum-sensitive relapsed breast cancer gene (BRCA)-mutated high grade serious epithelial ovarian, fallopian tube, or peritoneal cancer, who are in response to platinum-based chemotherapy. Over the last two years, several therapeutic indications have been added to the drug label, such as first-line platinum-sensitive BRCA-mutated high grade serious epithelial ovarian, fallopian tube, or peritoneal cancer, germline BRCA1/2-mutated, human epidermal growth factor 2 (HER2-)negative, locally advanced or metastatic breast cancer and BRCA1/2-mutated metastatic castration-resistant prostate cancer, who have progressed following prior therapy. Since olaparib is very expensive, this increase of treatment population will have a significant impact on health care expenditures.
To keep healthcare affordable and accessible for all patients, innovative strategies are warranted to reduce the dose of expensive drugs, without reduction of efficacy. For olaparib, pharmacokinetic (PK) boosting can be applied. PK boosting is the lay term for administering a non-therapeutic active strong inhibitor of a metabolic enzyme, for example the cytochrome p450 enzyme 3A (CYP3A), together with a therapeutic drug that is metabolized by the same enzyme. Boosting thus increases the concentration of the therapeutic drug and allows lower doses to be administered to patients. Hence, coadministration of a reduced dose of olaparib with cobicistat, a non-therapeutic, strong inhibitor of the CYP3A can lead to equivalent exposure to olaparib. Furthermore, inhibition of CYP3A could lead to less PK variability since metabolic capacity is a prominent cause for (intra- and inter-individual) variability in systemic exposure. Predictable olaparib exposure will reduce the number of patients who are unintentionally under- or overtreated. Lastly, tumor tissue itself may express CYP3A as a detoxification or resistance mechanism. Theoretically, PK boosting may also overcome CYP3A-mediated drug resistance.
The purpose of this study is to establish the efficacy, safety and feasibility of co-administering olaparib with the PK booster cobicistat with the aim to implement boosting approach for olaparib in routine practice. The study is subdivided in two parts. In part A of the study the equivalent exposure of boosted low dose olaparib is determined compared to the normal dose. In part B of the study, non-inferiority of the boosted olaparib regimen will be confirmed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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
- •Subjects who are able and willing to provide written informed consent prior to screening;
- •Age of 18 years or older;
- •Able to measure the outcome of the study in this subject.
- •Subjects who start or are on treatment with olaparib tablets 300mg twice daily, according to the drug label and physician's discretion;
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Subjects who start on treatment with olaparib tablets 300mg twice daily, according to the drug label and physician's discretion;
- •Expected to be on olaparib treatment for ≥ 3 months;
- •ECOG performance status of 0-3.
排除标准
- •Concurrent use of other anti-cancer therapies;
- •Concurrent use of potent inducers or inhibitors of the cytochrome p450 enzyme 3A3 (CYP3A4) as assessed with the Dutch drug database "G-Standaard" of the Royal Dutch Pharmacists Association(KNMP);
- •Known contra-indications for treatment with cobicistat in line with the summary of product characteristics;
- •Subjects with renal insufficiency defined as estimated glomerular filtration rate < 50 ml/min.
研究组 & 干预措施
Standard olaparib
Olaparib 300mg twice daily
干预措施: Olaparib (Drug)
Boosted olaparib
Olaparib 100mg twice daily + cobicistat 150mg twice daily
干预措施: Olaparib (Drug)
Boosted olaparib
Olaparib 100mg twice daily + cobicistat 150mg twice daily
干预措施: Cobicistat (Drug)
结局指标
主要结局
Part B: Progression-free survival (PFS)
时间窗: 12 months
PFS is defined as time from randomization until the date of either objective radiological disease progression, or biochemical progression combined with clinical progression or death.
Part B: Dose reductions
时间窗: 12 months
Number of patients who require a dose reduction due to toxicity.
Part A: Olaparib AUC0-12h
时间窗: 2 weeks
The Area-Under-the-Curve (AUC) 0-12h of olaparib.
次要结局
- Part A: Inter- and intrapatient variability of AUC0-12h(2 weeks)
- Part A: Adverse events(2 weeks)
- Part B: Patient satisfaction(12 months)
- Part B: Adverse events(12 months)
- Part B: ctDNA(12 weeks)
- Part B: Health status(12 months)
- Part B: Productivity costs(From date of randomization until the date of end-of-treatment, assessed up to 12 months)
- Part B: Medical consumption(From date of randomization until the date of end-of-treatment, assessed up to 12 months)