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SorAfenib Versus RADIOEMBOLIZATION in Advanced Hepatocellular Carcinoma (SARAH)

Primary Purpose

Liver Carcinoma

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
sorafenib
SIR-Sphere
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Liver Carcinoma focused on measuring Liver, HCC, Liver, interventional procedures, Liver, randomized studies, Liver, targeted therapy, Liver, RADIOEMBOLIZATION

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • CHU Amiens #2
  • CHU Angers #3
  • CHRU Besançon Hôpital Jean Minjoz #21
  • Hôpital Jean Verdier #25
  • Hôpital Côte de Nacre #4
  • Hôpital Antoine Béclère #29
  • Hopital beaujon #1
  • Henri Mondor #24
  • CHU Dijon Hôpital Bocage #22
  • CHU Grenoble #5
  • Hôpital Edouard Herriot #6
  • Lyon La croix Rousse #27
  • Institut Paoli Calmettes #7
  • CHU Marseille Hôpital La Timone #23
  • Hôpital Saint Eloi #8
  • Hôpital de Brabois #9
  • Hotel Dieu #10
  • Hôpital de L'Archet #11
  • Hôpital Européen Georges Pompidou #13
  • Hôpital Haut Leveque #14
  • CHU Poitiers La Milétrie
  • CHU Robert Debré #28
  • CHU Saint Etienne Hôpital Nord #17
  • Hôpital de Hautepierre #18
  • Paul Brousse #19
  • Institut Gustave Roussy #20

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

sorafenib group

radioembolization group

Arm Description

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.

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).

Outcomes

Primary Outcome Measures

Median overall survival time
Median overall survival time since randomisation

Secondary Outcome Measures

Common Terminology Criteria for Adverse Events
Adverse events reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0
Progression-free survival
Progression-free survival at 6 months
Response rate
Response rate (complete response, partial response, stable disease)
General and hepatic specific quality of life scores
General and hepatic specific quality of life scores
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

Full Information

First Posted
November 28, 2011
Last Updated
January 13, 2017
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Ministry of Health, France
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1. Study Identification

Unique Protocol Identification Number
NCT01482442
Brief Title
SorAfenib Versus RADIOEMBOLIZATION in Advanced Hepatocellular Carcinoma
Acronym
SARAH
Official Title
A Prospective Randomized Open-labeled Trial Comparing RADIOEMBOLIZATION With Yttrium 90 Microspheres and Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
December 2011 (undefined)
Primary Completion Date
April 2016 (Actual)
Study Completion Date
April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Ministry of Health, France

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Carcinoma
Keywords
Liver, HCC, Liver, interventional procedures, Liver, randomized studies, Liver, targeted therapy, Liver, RADIOEMBOLIZATION

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
496 (Actual)

8. Arms, Groups, and Interventions

Arm Title
sorafenib group
Arm Type
Active Comparator
Arm Description
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.
Arm Title
radioembolization group
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
sorafenib
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
SIR-Sphere
Intervention Description
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).
Primary Outcome Measure Information:
Title
Median overall survival time
Description
Median overall survival time since randomisation
Time Frame
36 months
Secondary Outcome Measure Information:
Title
Common Terminology Criteria for Adverse Events
Description
Adverse events reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0
Time Frame
36 months
Title
Progression-free survival
Description
Progression-free survival at 6 months
Time Frame
month 6
Title
Response rate
Description
Response rate (complete response, partial response, stable disease)
Time Frame
36 months
Title
General and hepatic specific quality of life scores
Description
General and hepatic specific quality of life scores
Time Frame
36 months
Title
Health care costs
Description
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
Time Frame
36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Valerie Vilgrain, PD, PhD
Organizational Affiliation
Department of radiology
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Amiens #2
City
Amiens
ZIP/Postal Code
80054
Country
France
Facility Name
CHU Angers #3
City
Angers
ZIP/Postal Code
49933
Country
France
Facility Name
CHRU Besançon Hôpital Jean Minjoz #21
City
Besançon
ZIP/Postal Code
25030
Country
France
Facility Name
Hôpital Jean Verdier #25
City
Bondy
ZIP/Postal Code
93140
Country
France
Facility Name
Hôpital Côte de Nacre #4
City
Caen
ZIP/Postal Code
14033
Country
France
Facility Name
Hôpital Antoine Béclère #29
City
Clamart
ZIP/Postal Code
92140
Country
France
Facility Name
Hopital beaujon #1
City
Clichy
ZIP/Postal Code
92110
Country
France
Facility Name
Henri Mondor #24
City
Créteil
ZIP/Postal Code
94000
Country
France
Facility Name
CHU Dijon Hôpital Bocage #22
City
Dijon
ZIP/Postal Code
21000
Country
France
Facility Name
CHU Grenoble #5
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
Hôpital Edouard Herriot #6
City
Lyon
ZIP/Postal Code
69003
Country
France
Facility Name
Lyon La croix Rousse #27
City
Lyon
ZIP/Postal Code
69004
Country
France
Facility Name
Institut Paoli Calmettes #7
City
Marseille
ZIP/Postal Code
13009
Country
France
Facility Name
CHU Marseille Hôpital La Timone #23
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
Hôpital Saint Eloi #8
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
Hôpital de Brabois #9
City
Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
Hotel Dieu #10
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Hôpital de L'Archet #11
City
Nice
ZIP/Postal Code
06002
Country
France
Facility Name
Hôpital Européen Georges Pompidou #13
City
Paris
ZIP/Postal Code
75908
Country
France
Facility Name
Hôpital Haut Leveque #14
City
Pessac
ZIP/Postal Code
33604
Country
France
Facility Name
CHU Poitiers La Milétrie
City
Poitiers
ZIP/Postal Code
86021
Country
France
Facility Name
CHU Robert Debré #28
City
Reims
ZIP/Postal Code
51100
Country
France
Facility Name
CHU Saint Etienne Hôpital Nord #17
City
Saint-Priest en Jarez
ZIP/Postal Code
42270
Country
France
Facility Name
Hôpital de Hautepierre #18
City
Strasbourg
ZIP/Postal Code
67098
Country
France
Facility Name
Paul Brousse #19
City
Villejuif
ZIP/Postal Code
94275
Country
France
Facility Name
Institut Gustave Roussy #20
City
Villejuif
ZIP/Postal Code
94805
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
34059326
Citation
Zarca K, Mimouni M, Pereira H, Chatellier G, Vilgrain V, Durand-Zaleski I; SARAH Trial Group. Cost-Utility Analysis of Transarterial Radioembolization With Yttrium-90 Resin Microspheres Compared With Sorafenib in Locally Advanced and Inoperable Hepatocellular Carcinoma. Clin Ther. 2021 Jul;43(7):1201-1212. doi: 10.1016/j.clinthera.2021.04.018. Epub 2021 May 28.
Results Reference
derived
PubMed Identifier
32602828
Citation
Hermann AL, Dieudonne A, Ronot M, Sanchez M, Pereira H, Chatellier G, Garin E, Castera L, Lebtahi R, Vilgrain V; SARAH Trial Group. Relationship of Tumor Radiation-absorbed Dose to Survival and Response in Hepatocellular Carcinoma Treated with Transarterial Radioembolization with 90Y in the SARAH Study. Radiology. 2020 Sep;296(3):673-684. doi: 10.1148/radiol.2020191606. Epub 2020 Jun 30.
Results Reference
derived
PubMed Identifier
29107679
Citation
Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H, Laurent V, Mathias E, Bronowicki JP, Tasu JP, Perdrisot R, Silvain C, Gerolami R, Mundler O, Seitz JF, Vidal V, Aube C, Oberti F, Couturier O, Brenot-Rossi I, Raoul JL, Sarran A, Costentin C, Itti E, Luciani A, Adam R, Lewin M, Samuel D, Ronot M, Dinut A, Castera L, Chatellier G; SARAH Trial Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6. Epub 2017 Oct 26.
Results Reference
derived
PubMed Identifier
25472660
Citation
Vilgrain V, Abdel-Rehim M, Sibert A, Ronot M, Lebtahi R, Castera L, Chatellier G; SARAH Trial Group. Radioembolisation with yttrium-90 microspheres versus sorafenib for treatment of advanced hepatocellular carcinoma (SARAH): study protocol for a randomised controlled trial. Trials. 2014 Dec 3;15:474. doi: 10.1186/1745-6215-15-474.
Results Reference
derived

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SorAfenib Versus RADIOEMBOLIZATION in Advanced Hepatocellular Carcinoma

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