BCLC Stage C HCC Clinical Trial
— SORBEOfficial title:
Population Pharmacokinetics and Pharmacodynamics of Sorafenib in HCC Patients With Child-Pugh B Liver Cirrhosis (SORBE-trial)
| Verified date | August 2019 |
| Source | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 5 |
| Est. completion date | March 2017 |
| Est. primary completion date | March 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility |
Inclusion Criteria: - Male or female, 18 years of age or older - Diagnosis of HCC: diagnosis based on the following criteria: 1. 1 radiologic technique: Focal lesion >1 cm with arterial hypervascularization in 4-phase CT or dynamic contrast enhanced MRI OR 2. 2 coincidental dynamic radiologic techniques (CT or MRI) in case one imaging technique is non-conclusive and lesion > 1 cm OR 3. 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 Exclusion Criteria: 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 |
| Country | Name | City | State |
|---|---|---|---|
| Netherlands | Academic Medical Center | Amsterdam |
| Lead Sponsor | Collaborator |
|---|---|
| Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | Erasmus Medical Center |
Netherlands,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Sorafenib exposure (AUC). | 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. | Through study completion, an average of 3 months | |
| Primary | Sorafenib peak plasma concentration | Peak plasma concentration (Cmax) for sorafenib. | Through study completion, an average of 3 months | |
| Primary | Sorafenib N-oxide exposure (AUC) | 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. | Through study completion, an average of 3 months | |
| Primary | Sorafenib N-oxide peak plasma concentration. | Peak plasma concentration (Cmax) for the main sorafenib metabolite (N-oxide sorafenib). | Through study completion, an average of 3 months | |
| Secondary | Adverse events according to CTCAE v4.0 | Adverse events are defined as any undesirable experience occurring to a subject during the study, whether or not considered related to sorafenib or drug cocktail. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded while receiving treatment and for 30 days after the last dose of Sorafenib, in order to detect delayed toxicity. Toxicity will be scored according NCI CTCAE version 4.0 The population PK analysis will be performed using nonlinear mixed effects modelling (NONMEM). Power calculations are not possible in NONMEM. Nevertheless, as a rule of thumb, 40 patients allow one to identify ca. 3 clinical significant correlations between PK parameters and patient characteristics. To be sure to have 40 evaluable patients we aim to recruit 45 patients. | Through study completion, an average of 3 months. | |
| Secondary | Progression-free survival | Progression free survival (PFS) is defined as the time from the date of start sorafenib to the first date of progressive disease (symptomatic or objective) or death to any cause, whichever occurs first. | Untill Progression or death (0-24 months) | |
| Secondary | Overall survival | Overall surval is defined as the time from start sorafenib, to death or censored at last follow-up. | Untill last follow-up or death (0-24 months) | |
| Secondary | CYP activity | In order to assess CYP3A4 activity prior to the start of sorafenib treatment, a single oral dose of 0.03 mg/kg midazolam will be administered. Substudy in 15 patients: Difference in exposure to 5 CYP probe drugs following administration of an oral cocktail of these agents after 4 weeks of sorafenib treatment in comparison with exposure to these cocktail probe drugs before initiation of sorafenib. |
4 weeks |