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Study title

Evaluation of Sorafenib in combination with local micro-therapy guided by Gd-EOB-DTPA enhanced MRI in patients with inoperable hepatocellular carcinoma


Short title

SORAMIC


Clinical study phase

II


Study objectives

Primary objectives:

1. In patients in whom local ablation therapy is appropriate (local ablation group), to determine if the sorafenib in combination with radiofrequency ablation (RFA) prolongs the time-to-recurrence (TTR) in comparison with RFA + placebo.
2. In patients in whom RFA is NOT appropriate (palliative treatment group), to determine if the combination of yttrium-90 microspheres (SIRT) + sorafenib improves the overall survival (OS) in comparison to sorafenib alone.
3. To confirm in a 2-step procedure that Primovist®-enhanced MRI is non-inferior (first step) or superior (second step) compared with contrast-enhanced multislice CT for stratification of patients to a palliative vs. local ablation treatment strategy.


The overall study is successful, if the primary objectives 1 OR 2 are met, AND Primovist®-enhanced MRI is at least non-inferior to contrast-enhanced CT for treatment stratification.


Secondary objectives:

  • to assess health-related quality of life
  • to compare the number of detected lesions and the diagnostic confidence in Primovist-enhanced MRI with contrast-enhanced CT
  • to compare Primovist-enhanced MRI with contrast-enhanced CT regarding the detection of recurrence (patients in the local ablation group only)
  • to assess the safety of the combination of RFA + sorafenib in comparison to RFA + placebo
  • to assess the safety of the combination of SIR-Spheres therapy and sorafenib in comparison to sorafenib alone
  • to assess in the palliative study group overall survival separately for patients with and without portal thrombosis

Test product

Sorafenib (Nexavar® as approved for marketing)

SIR-Spheres® (as approved for marketing; medical device)

Gd-EOB-DTPA (Primovist® as approved for marketing)


Reference product

n.a.


Indication

Hepatocellular carcinoma (HCC)


Diagnosis and main criteria for inclusion

Patients with a first diagnosis of HCC without prior therapy and without extrahepatic metastases


Study design

Randomized, multi-center


Methodology

Patients with a diagnosis of hepatocellular carcinoma will receive either

  • local ablation therapy of liver lesions by radiofrequency ablation followed by sorafenib or placebo (local ablation group), or
  • radioembolization (SIRT) + sorafenib or sorafenib alone (palliative treatment group).

In each study group, patients will be randomized to one of the 2 treatment arms following a pre-defined randomi­zation plan.  Randomization will be on a 1:1 basis in the local ablation group and on the basis of 10 (sorafenib only) : 11 (SIRT + sorafenib) in the palliative treatment group.
Patients in the local ablation group will be followed at 2 months intervals for recurrence and overall survival, patients in the palliative treatment group will be followed for overall survival.  Follow-up in each study group will end 24 months after inclusion of the last patient into the respective study group.
The assignment of patients to the local ablation or palliative study group will be based on the ablative potential of RFA (local ablation if 4 tumors, each 5 cm in size).  Diagnostic imaging will be used to guide this decision.  The assignment to the local ablation or the palliative treatment group will be made by the local investigator.
As a sub-study, all patients will undergo Primovist®-enhanced MRI in addition to contrast-enhanced CT before assignment to one treatment group.  The goal of the sub-study is to assess the value of Primovistâ-enhanced MRI to correctly stratify patients for a local ablation or palliative treatment strategy.  Primovistâ-enhanced MRI will be compared with contrast-enhanced multislice CT using a truth panel assessment as the standard of reference.  In addition, Primovist-enhanced MRI and contrast-enhanced CT will be obtained during follow-up of patients in the local ablation group to assess its potential for detection of recurrence.

Type of control

  • Group receiving placebo (local ablation group)
  • Group receiving no SIRT (palliative treatment group)
  • CT as comparator, truth panel assessment as standard of reference (diagnostic sub-study)

Planned study dates

First Patient First Visit

December 1, 2010

Last Patient First Visit

March 2016

Last Patient Last Visit

March 2018

Planned number of centers

40


Planned number of countries

11


Number of patients

Total

665 patients (incl. expected drop-out)

Local ablation group

290 valid pats.
(incl. expected drop-out)

Palliative study group

375 valid pats.
(incl. expected drop-out)

Primary variables

  • TTR (local ablation group)
  • OS (palliative treatment group)
  • number of correct assignments to a local ablation / palliative treatment strategy (diagnostic sub-study)

Plan for statistical analysis

The analysis will be performed after the completion of the study according to a separate statistical analysis plan and the statistical methods section of this protocol.