Population Pharmacokinetics and Pharmacodynamics of Sorafenib in HCC Patients With Child-Pugh B Liver Cirrhosis (SORBE-trial)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Sorafenib exposure (AUC).
研究概览
简要总结
Sorafenib has proven efficacy in advanced hepatocellular carcinoma (HCC). Most patients with HCC have impaired liver function due to underlying liver cirrhosis. The severity of liver cirrhosis might have implications on sorafenib metabolism. To date, no data showing unequivocal activity and tolerability of sorafenib in patients with moderate cirrhosis (Child-Pugh (CP)-B) have been published.
To specifically address this issue, this study aims to explore population pharmacokinetics of sorafenib and to explore the relationship between sorafenib exposure and its efficacy and toxicity in CP-B patients with irresectable HCC.
详细描述
Study design:
This is a prospective, open-label, national, multicenter observational study to investigate the tolerability, pharmacokinetics and clinical activity of sorafenib and its metabolites in patients with HCC and CP-B liver cirrhosis
Study population:
45 Patients with BCLC stage C HCC and CP-B liver cirrhosis
Treatment:
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
- 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
- •Male or female, 18 years of age or older
- •Diagnosis of HCC: diagnosis based on the following criteria:
- •1 radiologic technique: Focal lesion >1 cm with arterial hypervascularization in 4-phase CT or dynamic contrast enhanced MRI OR
- •2 coincidental dynamic radiologic techniques (CT or MRI) in case one imaging technique is non-conclusive and lesion > 1 cm OR
- •biopsy proven HCC
- •Patients with advanced HCC - BCLC stage C
- •Cancer related symptoms (symptomatic tumors, ECOG Performance status 1-2), macrovascular invasion (either segmental or portal invasion) or extrahepatic spread (lymph node involvement or distant metastases)
- •Not eligible for TACE (; i.e. diffuse tumors, tumors larger than 5 cm)
- •Not eligible for curative resection or RFA
- •Patients with CP-B liver cirrhosis (CP-B score 7 or 8)
- •Capable of giving written informed consent
- •History of organ transplant (including prior liver transplantation) is allowed
- •HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease (rheumatoid arthritis) is allowed
排除标准
- •Subjects will not be enrolled in the study if any of the following criteria apply:
- •CP-B9 liver cirrhosis
- •CP-C liver cirrhosis
- •Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial
- •Concurrent antitumoral treatment for HCC or other malignancies
- •Not eligible for sorafenib treatment
- •Bilirubin > 51 micromol/L
- •If female, pregnant or breast feeding (females of child-bearing potential must use adequate contraception and must have a negative pregnancy test performed within 7 days prior to inclusion into this study)
- •If male, not using adequate birth control measures
- •One or more of the following: - WBC <2,500 cells/mm3, - ANC <1,500 cells/mm3, - platelets <50,000/mm3,
- •ECOG performance status >2
- •Patients with known GFR <30 mL/min/1.73m2
- •Significant cardiovascular disease; e.g., myocardial infarction within 6 months of inclusion, chronic heart failure (New York Heart Association class III or IV), unstable coronary artery disease
- •Uncontrolled hypertension i.e. systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mm Hg despite optimal medical management (2 classes of antihypertensive drugs)
- •History of hemorrhage / bleeding events of grade 3 or worse within 30 days before inclusion into this study
- •Previous variceal bleeding within the past 3 months
- •Additional exclusion criteria for cocktail test
- •Consumption of grapefruit or grapefruit juice and/or kumquats, pummelos, exotic citrus fruit (i.e., star fruit, bitter melon) or grapefruit hybrids from seven days prior to the first dose of cocktail.
- •Use of herbal medicine or medication that induce or inhibit CYP3A4/5, CYP2C9, CYP2D6, CYP1A2 and CYP2C19
- •Use of omeprazole, warfarin, metoprolol, caffeine or midazolam (=medication of the probe cocktail)
- •Concurrent anticoagulant therapy
研究组 & 干预措施
Sorafenib with midazolam clearance test
Before start of treatment patients receive a single oral dose of midazolam to phenotype CYP3A4 activity. Blood samples will be taken at several time points to measure sorafenib and midazolam concentrations.
Patients will receive sorafenib at a starting dose of 200 mg twice daily. In the absence of toxicity dosage will be escalated with weekly intervals up to 400 mg BID (max dose).
干预措施: Sorafenib (Drug)
Sorafenib with midazolam clearance test
Before start of treatment patients receive a single oral dose of midazolam to phenotype CYP3A4 activity. Blood samples will be taken at several time points to measure sorafenib and midazolam concentrations.
Patients will receive sorafenib at a starting dose of 200 mg twice daily. In the absence of toxicity dosage will be escalated with weekly intervals up to 400 mg BID (max dose).
干预措施: Midazolam clearance test (Other)
Sorafenib with CYP cocktail test
In this subgroup of 15 patients (in the Academic Medical Center Amsterdam), the midazolam test will be replaced by an oral cocktail of subclinical doses of caffeine, midazolam, omeprazole, warfarin and metoprolol and will be repeated after 4 weeks of treatment to assess the influence of sorafenib on cytochrome P450 (CYP) 1A2, 3A4, 2C19, 2C9 and 2D6 activity, respectively.
Patients will receive sorafenib at a starting dose of 200 mg twice daily. In the absence of toxicity dosage will be escalated with weekly intervals up to 400 mg BID (max dose).
干预措施: Sorafenib (Drug)
Sorafenib with CYP cocktail test
In this subgroup of 15 patients (in the Academic Medical Center Amsterdam), the midazolam test will be replaced by an oral cocktail of subclinical doses of caffeine, midazolam, omeprazole, warfarin and metoprolol and will be repeated after 4 weeks of treatment to assess the influence of sorafenib on cytochrome P450 (CYP) 1A2, 3A4, 2C19, 2C9 and 2D6 activity, respectively.
Patients will receive sorafenib at a starting dose of 200 mg twice daily. In the absence of toxicity dosage will be escalated with weekly intervals up to 400 mg BID (max dose).
干预措施: CYP cocktail clearance test (Other)
结局指标
主要结局
Sorafenib exposure (AUC).
时间窗: Through study completion, an average of 3 months
Area under the plasma concentration versus time curve (AUC). Exposure and intra- and inter-patient variability in exposure to sorafenib. The population PK analysis will be performed using nonlinear mixed effects modelling (NONMEM). Predictive factors for sorafenib exposure, i.e. bilirubin, CYP3A4 activity, shall be explored.
Sorafenib N-oxide peak plasma concentration.
时间窗: Through study completion, an average of 3 months
Peak plasma concentration (Cmax) for the main sorafenib metabolite (N-oxide sorafenib).
Sorafenib peak plasma concentration
时间窗: Through study completion, an average of 3 months
Peak plasma concentration (Cmax) for sorafenib.
Sorafenib N-oxide exposure (AUC)
时间窗: Through study completion, an average of 3 months
Area under the plasma concentration versus time curve (AUC) for the main sorafenib metabolite (N-oxide sorafenib). Exposure and intra- and inter-patient variability in exposure to N-oxide sorafenib. The population PK analysis will be performed using nonlinear mixed effects modelling (NONMEM). Predictive factors for N-oxide sorafenib exposure, i.e. bilirubin, CYP3A4 activity, shall be explored.
次要结局
- CYP activity(4 weeks)
- Adverse events according to CTCAE v4.0(Through study completion, an average of 3 months.)
- Progression-free survival(Untill Progression or death (0-24 months))
- Overall survival(Untill last follow-up or death (0-24 months))
研究者
Heinz-Josef Klumpen
Medical Oncologist & Principle Investigator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)