LANEX: Neoadjuvant Sorafenib Therapy Prior to Laser Ablation for Hepatocellular Carcinoma

Sponsor

Cardarelli Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT01507064

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether neoadiuvant therapy with sorafenib increases the efficacy of thermal ablation in inducing the necrosis of hepatocellular carcinoma.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: Sorafenib Procedure: laser ablation (LA)	Phase 2

Detailed Description

BACKGROUND AND AIM Image-guided laser ablation (LA), minimally invasive procedure, is a potentially viable treatment option for achieving focal thermal destruction of hepatocellular carcinoma (HCC) that cannot be treated with surgery. Both techniques are effective for the destruction of small (<3 cm) tumors, but the success rate for index tumors larger than 4 cm in diameter is lower. A cause of the difficulty in treating larger tumors is represented by the heat-sink effect of tumor blood flow that limits the size of tumor ablation by drawing heat away from the tumor nodule. Surgical (Pringle maneuver) and endovascular (transarterial chemoembolization) techniques have been used to reduce the tumor blood flow during or before thermal ablation, but these techniques require invasive procedures that may decrease the patient acceptance and increase the risk of complications. Sorafenib is a multikinase inhibitor that has been approved for the treatment of advanced HCC. One of the main effect of this drug is to block vascular endothelial growth factor (VEGF) pathway, Flt-3, c-KIT, and fibroblast growth factor receptor 1, that have been shown to mediate tumor angiogenesis, reducing intratumoral blood flow. An experimental study in mice with renal cell carcinoma implanted subcutaneously, showed that treatment with sorafenib before ablation resulted in markedly decreased cancer microvessel density and significantly larger zones of radiofrequency-induced coagulation necrosis (1).

The purpose of this study is to determine if sorafenib improves the effectiveness of laser ablation (LA) for the treatment of HCC larger than 4cm in size.

Hakimé A, Hines-Peralta A, Peddi H, Atkins MB, Sukhatme VP, Signoretti S, Regan M, Goldberg SN. Combination of Radiofrequency Ablation with Antiangiogenic Therapy for Tumor Ablation Efficacy: Study in Mice. Radiology 2007, 244, 464-470.

STUDY DESIGN

Participants will be randomized to receive either sorafenib (400mg twice a day) or placebo continuously for 4 weeks (on days 1-28). LA will be performed on day 29. On days 0 and 28, and 1, 6, and 12 months after LA, patients will undergo to a physical exam. Adverse events will be recorded using a pre-planned questionnaire in accordance with the "common toxicity criteria".

Occurrence and characteristics of postablation syndrome will also be recorded. During a six-month period, if clinically indicated LA procedures preceded by a four-week sorafenib treatment, may be repeated up to three times.

Laboratory values will be assessed on days 0 and 28, and 1, 6, and 12 months after the first LA procedure.

Upper gastrointestinal endoscopy will be done before starting drug treatment. A tumor biopsy will be obtained at the time of the first LA. A CT or MRI scan will be performed at the time of inclusion in the study, at 1, 6, and 12 months after LA.

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Controlled Phase II Trial Of Neoadjuvant Sorafenib Therapy Prior to Thermal Ablation for Hepatocellular Carcinoma More Than 4 cm in Size

Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Sep 1, 2015

Actual Study Completion Date :

Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group A Patients who undergo to LA without sorafenib pretreatment	Procedure: laser ablation (LA) For LA, we use a commercially available system (Echolaser XVG system, Esaote El.En., Florence, Italy) and four optical fibers,inserted into the tumor through four 21-gauge needles. The tips of the needles will be positioned at a distance of 15mm from each other. When, after LA treatments, CT or MRI findings show a residual nodule activity of 10% or less, percutaneous ethanol injection may be done. If the residual activity is of 50% or more transarterial chemoembolization may be used.
Experimental: Group B Patients who are treated with sorafenib before LA	Drug: Sorafenib tablets 200mg dosage: 400mg bid duration: 4 weeks Other Names: Nexavar Procedure: laser ablation (LA) For LA, we use a commercially available system (Echolaser XVG system, Esaote El.En., Florence, Italy) and four optical fibers,inserted into the tumor through four 21-gauge needles. The tips of the needles will be positioned at a distance of 15mm from each other. When, after LA treatments, CT or MRI findings show a residual nodule activity of 10% or less, percutaneous ethanol injection may be done. If the residual activity is of 50% or more transarterial chemoembolization may be used.

Arm

Intervention/Treatment

Active Comparator: Group A

Patients who undergo to LA without sorafenib pretreatment

Procedure: laser ablation (LA)

For LA, we use a commercially available system (Echolaser XVG system, Esaote El.En., Florence, Italy) and four optical fibers,inserted into the tumor through four 21-gauge needles. The tips of the needles will be positioned at a distance of 15mm from each other. When, after LA treatments, CT or MRI findings show a residual nodule activity of 10% or less, percutaneous ethanol injection may be done. If the residual activity is of 50% or more transarterial chemoembolization may be used.

Experimental: Group B

Patients who are treated with sorafenib before LA

Drug: Sorafenib

tablets 200mg dosage: 400mg bid duration: 4 weeks

Other Names:

Nexavar

Procedure: laser ablation (LA)

Outcome Measures

Primary Outcome Measures

Effectiveness of sorafenib in increasing the effectiveness of laser ablation (LA) [1 year]
Measures: complete tumor ablation rate (according to the mRECIST), time-to-recurrence (in complete response subgroup), time-to-progression (in partial response subgroup).

Secondary Outcome Measures

Safety of sorafenib treatment prior to LA. [6 months]
Measure: incidence and grade of adverse events in patients treated with sorafenib (group B)
Survival in the two treatment groups [2 years]
Measured from the date of LA until the date of death or last visit

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18-80 years
ECOG = 0 or 1
No liver decompensation (Child-Pugh <8), bilirubin <3mg/dL
Patients with unresectable HCC or who refused surgery
Confirmed HCC by pathology or by AASLD imaging guidelines
At least one HCC nodule (index tumor) accurately measured as 4-8cm in diameter on baseline imaging
No prior therapy for the index tumor
No prior systemic treatment for HCC within 4 weeks of study entry
LA clinically indicated for index tumor
Hemoglobin >9.0 g/dl; Platelet count correctable to >50,000/mm3; INR correctable to <2.0.

Exclusion Criteria:

Other severe concomitant diseases that may reduce life expectancy
Participants currently receiving any other study agents
Cancer vascular invasion or extrahepatic metastasis
Uncontrolled hypertension
Thrombotic events or myocardial infarction within the past 6 months
Hemorrhage/bleeding event within 4 weeks
Evidence of severe or uncorrectable bleeding diathesis or coagulopathy
Contraindication to or inability to undergo the LA procedure
Human immunodeficiency virus (HIV) infection
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study.