Clinical trial NCT02834546: Correlation Between Sorafenib Plasma Concentrations, Toxicity and Disease Control Rate in Patients Treated by Sorafenib for Hepatocellular Carcinoma
Official title: Correlation Between Sorafenib Plasma Concentrations, Toxicity and Disease Control Rate in Patients Treated by Sorafenib for Hepatocellular Carcinoma
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hepatocellular Carcinoma (HCC)
Keywords: Hepatocellular Carcinoma
Sorafenib
Toxicity
Plasmatic concentration
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
First posted: 2016-07-15
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patient with HCC from 5 care centers in France for whom the indication of a first treatment with sorafenib was decided and who will be treated according to the recommendations of drug SmpC

Brief summary: The aim of this pilot study is to correlate the sorafenib plasma concentration to observed toxicity and to the disease control rate in 100 patients undergoing a palliative treatment of hepatocellular carcinoma (HCC). If some correlations are observed, we will consider planning a larger interventional study to adjust sorafenib daily dose to plasma concentration.

Detailed description: Sorafenib is the standard of care for the palliative treatment of HCC. The recommended dose of sorafenib in patients with HCC is 400 mg twice daily. Sorafenib dose-limiting toxicities include diarrhea, arterial hypertension and hand-foot syndrome. Owing a large inter-patient variability (near 50%) of sorafenib Area Under the Curve (AUC) over 12h, an over-exposure to sorafenib could explain acute toxicity. On the other hand, a suboptimal exposure could result in an insufficient anti-tumor activity as suggested by a recent study. This inter-patient variability of sorafenib pharmacokinetic is especially relevant in HCC. Indeed, most of HCC are developed on cirrhotic liver with often an impaired liver function, a decrease of albuminemia and sometimes ascitis. All these parameters are likely to impact the sorafenib pharmacokinetic. The aim of this pilot study is to correlate the sorafenib plasma concentration to observed toxicity and to the disease control rate in 100 patients.

The dose of sorafenib will be the recommended dose: 400 mg twice daily. Sorafenib daily doses will be only adjusted by the clinician on adverse event. Values of sorafenib AUC will not be transmitted to clinician.

Patients will be followed during 12 months with 5 visits: Week 4, Week 8, Week 16, Month 6 and Month 12. Adverse event related to sorafenib will be recorded and graded according to the NCI-CTC for Adverse Event during all the study period. Sorafenib plasma concentrations will be assessed at 4, 8 and 16 weeks. An additional dosage could be performed between W1 and W4, before dose modification, if a dose modification is necessary due to adverse events before W4.

Eligibility criteria: Inclusion Criteria:

* Subjects \> 18 years age
* Possibility of regular monitoring
* Ability to understand and willingness to sign written informed consent.
* Hepatocellular carcinoma histologically diagnosed or in case of inability to perform a histology by non-invasive radiological criteria endorsed by EASL/AASLD (a) presence of known cirrhosis and (b) identification of a focal hepatic lesion measuring at least 1cm in diameter with contrast uptake in the arterial phase and rapid wash out in the venous /late phase on two imaging techniques
* Patient not eligible for curative treatment (transplantation, resection, destruction or percutaneous chemo-embolization) or HCC still evolving after failure of a specific treatment
* ECOG ≤ 2
* Child-Pugh A or B
* Score BCLC B or C

Exclusion Criteria:

* Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study
* Cirrhosis CHILD C
* Score BCLC D
* ECOG \> 2
* Digestive bleeding within 30 days before inclusion
* Subject has had a liver transplant or waiting for a liver transplant
* Subject previously treated with sorafenib
* Childbearing or breastfeeding women

Primary outcomes:
measure: Adverse events related to Sorafenib needing a dose adjustment or a symptomatic medication
timeFrame: Up 8 weeks after sorafenib treatment introduction
Secondary outcomes:
measure: Adverse events notification
timeFrame: Week 8, 16, month 6 and 12 after sorafenib treatment introduction
measure: Radiological response assessed by scan or MRI
timeFrame: Week 8, 16, month 6 and 12 after sorafenib treatment introduction
measure: Progression-free survival time
timeFrame: Up to month 12 after sorafenib treatment introduction
measure: Overall survival
timeFrame: Up to month 12 after sorafenib treatment introduction
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
city: Limoges
country: France
facility: CHU de Limoges
city: Montpellier
country: France
facility: CHU de Montpellier
city: Pessac
country: France
facility: CHU de Bordeaux
city: Toulouse
country: France
facility: CHU de Toulouse
Study officials:
affiliation: Unité de Soutien Méthodologique à la Recherche clinique et épidémiologique du CHU de Bordeaux
name: Eric FRISON, MD
role: STUDY_CHAIR
References: