SorAfenib Versus RADIOEMBOLIZATION in Advanced Hepatocellular Carcinoma

Liver Carcinoma Clinical Trial

— SARAH  

Official title:

A Prospective Randomized Open-labeled Trial Comparing RADIOEMBOLIZATION With Yttrium 90 Microspheres and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01482442
• Other study ID #: P101103
• Status: Completed
• Phase: Phase 3
• First received: November 28, 2011
• Last updated: January 13, 2017
• Start date: December 2011
• Est. completion date: April 2016

Study information

• Verified date: January 2017
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether RADIOEMBOLIZATION with 90 Yttrium microspheres is more effective on overall survival in advanced Hepatocellular carcinoma (HCC) with or without portal venous obstruction and no extrahepatic extension than sorafenib which is now the standard treatment of advanced HCC.

Description:

Background: In patients with advanced hepatocellular carcinoma, sorafenib is now the standard treatment with an increased median overall survival but an overall incidence of treatment-related adverse events of 80%. There is growing interest for RADIOEMBOLIZAION with 90 Yttrium microspheres. It involves infusion of embolic microparticles of glass or resin impregnated with the isotope yttrium-90 through a catheter directly into the hepatic arteries. A substantial number of open-label single-group studies showed supporting evidence for a potential efficacy on overall survival and acceptable or low toxicity. Trial design: multicenter, prospective, controlled, open label randomized trial of Y90 RADIOEMBOLIZATION versus sorafenib. Participants: Adult patients with 1) advanced HCC according to BCLC staging system (stage C) with or without portal vein thrombosis 2) ECOG performance status of 2 or less 3) adequate haematological, renal and hepatic functions 4) liver cirrhosis Child Pugh A - B7 and 5) no extrahepatic metastasis. Interventions: In the sorafenib group, patients will receive continuous oral treatment with 400 mg of sorafenib twice daily. In the Y90 RADIOEMBOLIZATION group, patients will first undergo angiography and scintigraphy for eligibility assessment (absence of or acceptable lung shunting) and preconditioning (embolization). RADIOEMBOLIZATION therapy with infusion of Y90 microspheres will be performed secondly. Objectives: The primary objective is to compare the efficacy of Y90 RADIOEMBOLIZATION to sorafenib in the treatment of advanced hepatocellular carcinoma. Secondary objectives include the comparison of safety profiles, quality of life and health care costs between the two therapeutic groups. Outcomes: The primary endpoint is the median overall survival time. Secondary endpoints include adverse events reported according to the NCI CTC, progression-free survival at 6 months, response rates, general and hepatic-specific quality of life scores, health care costs which comprise the MICROCOSTING of Y90 RADIOEMBOLIZATION from the viewpoint of the hospital and the full cost of each strategy. Sample size: 400 participants (200 par arm). The trial have 80% power to detect a clinically meaningful increase in median survival time of 4 months between sorafenib (expected median survival time 10.7 months) and Y90 RADIOEMBOLIZATION (expected median survival time 15 months) with a two-tailed type I error risk of 5%. Randomization: 1 to 1 randomization will be stratified according to recruiting center, ECOG performance status (a score of 0 vs. a score of 1 or 2), presence or absence of macroscopic vascular invasion (obstruction of portal vein or any branch vs none) and previous chemoembolisation failure . Randomly permuted blocks of random sizes will be used. Study duration and Setting: Accrual period 24 months. Additional follow-up period: 12 months. 14 centres involving both clinicians (hepatologists, hepatobiliary surgeons, and oncologists) and radiologists and Nuclear medicine physicians on each site.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 496
• Est. completion date: April 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histological or cytological diagnosis or meet the AASLD criteria for diagnosis of HCC and at least one uni-dimensional lesion measurable according to RECIST criteria by CT-scan or MRI

• Adult over 18 years old and estimated life expectancy over 3 months

• Patient with advanced HCC according to BCLC staging system (stage C) with or without portal vein thrombosis, not eligible for surgical resection, liver transplantation nor radiofrequency ablation OR patient with progression or recurrence of HCC after surgical or locoregional treatment not eligible for surgical resection, liver transplantation nor radiofrequency ablation OR patients in whom chemoembolisation has failed after two courses (patients who have received only one course of chemoembolisation are eligible if the failure of the first round shows that a second round will have no more impact; patients who have received more than two courses of chemoembolisation are still eligible if the arterial network is perfectly normal on a CT scan in the arterial phase). Failure is defined as the absence of an objective response after two courses of treatment in the treated nodule (objective response according to modified RECIST criteria and/or EASL criteria).

• ECOG performance status under or equals 1

• Adequate haematological function: Hb over or equals 9g/100mL, absolute neutrophil count over or equals 1 500/mm3, platelet count over or equals 50 000/mm3

• Adequate renal function; serum creatinine under 150µmol/L

• Bilirubin under or equals 50 µmol/L, AST or ALT uner or equals 5 x ULN, INR under or equals 1.5

• Liver cirrhosis Child Pugh A - B7

• written informed consent

Exclusion Criteria:

• Another primary tumour, with the exception of conventional basal cell carcinoma or superficial bladder neoplasia

• Extrahepatic metastasis

• Advanced HCC previously treated

• Advanced liver disease with Child-Pugh score over 7 or active gastrointestinal bleeding or encephalopathy or ascites refractory to diuretic therapy Women who are pregnant or breast feeding

• Allergy to contrast media

• Contraindication to hepatic artery catheterisation, such as severe peripheral vascular disease precluding catheterisation

• Psychiatric or other disorder likely to impact on informed consent

• Patient unable and/or unwilling to comply with treatment and study instructions

• Patient unable to swallow oral medications

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Liver Carcinoma

Intervention

Drug:
• sorafenib
Patients will receive continuous oral treatment with 800 mg of sorafenib daily (Nexavar, Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals). Treatment interruptions and dose reductions (to 400 mg once daily) will be permitted for drug-related adverse effects. At the discretion of the investigator, the dose may be re-escalated to after the resolution of the adverse event.
• SIR-Sphere
The first step will check patient eligibility and prepare conditioning by performing selective mesenteric and hepatic angiography (to document the arterial tumor supply and to occlude extrahepatic vessels) and 99mTc-macroaggregated albumin scintigraphy. The second step is RADIOEMBOLIZATION therapy. One to two weeks after patient eligibility and conditioning, treatment is performed with SIR-Sphere (SIRTEX Medical Ltd.,Lane Cove,Australia).

Locations

Country	Name	City	State
France	CHU Amiens #2	Amiens
France	CHU Angers #3	Angers
France	CHRU Besançon Hôpital Jean Minjoz #21	Besançon
France	Hôpital Jean Verdier #25	Bondy
France	Hôpital Côte de Nacre #4	Caen
France	Hôpital Antoine Béclère #29	Clamart
France	Hopital beaujon #1	Clichy
France	Henri Mondor #24	Créteil
France	CHU Dijon Hôpital Bocage #22	Dijon
France	CHU Grenoble #5	Grenoble
France	Hôpital Edouard Herriot #6	Lyon
France	Lyon La croix Rousse #27	Lyon
France	CHU Marseille Hôpital La Timone #23	Marseille
France	Institut Paoli Calmettes #7	Marseille
France	Hôpital Saint Eloi #8	Montpellier
France	Hôpital de Brabois #9	Nancy
France	Hotel Dieu #10	Nantes
France	Hôpital de L'Archet #11	Nice
France	Hôpital Européen Georges Pompidou #13	Paris
France	Hôpital Haut Leveque #14	Pessac
France	CHU Poitiers La Milétrie	Poitiers
France	CHU Robert Debré #28	Reims
France	CHU Saint Etienne Hôpital Nord #17	Saint-Priest en Jarez
France	Hôpital de Hautepierre #18	Strasbourg
France	Institut Gustave Roussy #20	Villejuif
France	Paul Brousse #19	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Ministry of Health, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Median overall survival time	Median overall survival time since randomisation	36 months
Secondary	Common Terminology Criteria for Adverse Events	Adverse events reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0	36 months
Secondary	Progression-free survival	Progression-free survival at 6 months	month 6
Secondary	Response rate	Response rate (complete response, partial response, stable disease)	36 months
Secondary	General and hepatic specific quality of life scores	General and hepatic specific quality of life scores	36 months
Secondary	Health care costs	Health care costs which comprise 2 parts: 1) the microcosting of Y90 radioembolization from the viewpoint of the hospital and 2) the full cost of each strategy	36 months