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

Primary hepatocellular carcinoma (HCC) is the fifth most common cancer in the
world, with over 1.25 million cases of HCC occurring annually. HCC is a leading
cause of cancer-related mortality in both men and women worldwide with an
increasing incidence rate and a predominance in developing countries. Only
about 30% of patients are diagnosed early enough to benefit from potentially
curative therapies, such as surgical resection, allogeneic liver
transplantation or percutaneous ablation, which afford 5-year survival rates of
50-75 %.
Median survival in the absence of treatment is 3-6 months; actuarial survival
is 31% at one year, 8% at two years, and <3% at three years in the USA (SEER1).
Most HCC patients are diagnosed at intermediate to advanced stages of disease,
for which no generally accepted standard therapy exist, apart from sorafenib.
HCC generally leads to death as a consequence of local tumor growth, tissue
destruction and liver destruction, rather than widespread extrahepatic disease.
Once a diagnosis has been made, patient prognosis varies according to disease
stage and treatment received. The main prognostic factors are related to tumor
status (defined by the number and size of nodules, the presence or absence of
vascular invasion, and the presence or absence of extrahepatic spread), liver
function (defined by Child*Pugh class, serum bilirubin and albumin levels, and
portal hypertension), and general health status (defined by Eastern Cooperative
Oncology Group [ECOG] classification and presence of symptoms). Etiology is not
an independent prognostic factor.
Several classification systems are available for HCC. The Barcelona Clinic
Liver Cancer (BCLC) classification has emerged during recent years and has been
used to link stage stratification with a recommended treatment strategy, and to
define a standard of care for each tumor stage. Depending on tumor stage,
different treatment options are available: local surgical resection, orthotopic
liver transplantation, percutaneous ethanol injection (PEI), radiofrequency
ablation (RFA), brachytherapy (BT), and transarterial chemoembolization (TACE).
Recently, the multikinase inhibitor sorafenib and Selective Internal Radiation
Therapy (SIRT) have shown promise in advanced liver cancer.

Treatment strategy in early HCC aims at the local removal of the tumor and
represents a potentially curative treatment option (resection, liver
transplantation, PEI, RFA, BT). Patients in intermediate and advanced stage of
HCC receive treatment with palliative intent (TACE, sorafenib, SIRT). It is the
goal of this study to examine in a *real world setting* the prospects of two
treatment options: sorafenib as an adjuvant therapy after local tumor resection
for patients with early HCC, and SIRT as an option for patients with advanced
HCC. The selection of an appropriate treatment for individual patients depends
largely on the number and size of liver lesions. Diagnostic imaging using CT
and MRI plays a major role in this respect. In the past several years, the
liver-specific MR contrast agent Primovist has received marketing authorization
throughout (most of) Europe for the detection and characterization of liver
lesions. In a diagnostic sub-study, Primovist-enhanced MRI will be compared
with contrast-enhanced CT with regard to the detection of liver lesions,
appropriate assignment to treatment group (local ablation or palliative), and
the detection of tumor recurrence.

Randomized, multi-center
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 Primovist®-enhanced MRI to correctly
stratify patients for a local ablation or palliative treatment strategy.
Primovist®-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.

SIRT (palliative arm)
One SIRT prescription consists of the pre-treatment assessment followed by one
or 2 treatment sessions.
The aim of pre-treatment assessment of the hepatic arterial vasculature is to
ensure delivery of the microspheres to the target. It consists of a detailed
hepatic and visceral angiography together with the assessment of the
hepatic-pulmonary shunt fraction. In angiography, the superior mesenteric,
celiac and hepatic arterial branches are evaluated and parasitic supply to
tumor nodules via non-hepatic vessels is excluded. Evaluation includes a
determination of the arterial location and any consequent necessity for
coil-embolization of the gastroduodenal artery, right gastric artery and any
other accessory arteries to prevent inadvertent administration of microspheres
into the gastrointestinal tract or pancreas. In addition, parasitic
extrahepatic supply should be coil-embolized.
The presence of variant hepatic arterial anatomy may alter the treatment plan.
Treatment with SIR-Spheres® microspheres is precluded by stenosis or slow
antegrade flow within the hepatic arteries that results in embolic occlusion of
the vessel and, therefore, reflux into extrahepatic territories.
Hepatopulmonary shunting secondary to tumor-related pathologic arteriovenous
pathways, as well as reflux toward the gastrointestinal region, may be detected
in scintigraphy with the injection of 148 MBq (4 mCi) of 99mTc-MAA as a
SIR-Spheres® microspheres surrogate into the hepatic arterial territory
(scintigraphy is to be performed after embolization of vessels, if applicable).
The regions of interest are the counts from the lungs and from the liver.
Patients in whom the shunt fraction indicates potential exposure to the lung to
an absorbed radiation dose of more than 30 Gy should be excluded from treatment
with SIR-Spheres® microspheres.
Patients who are randomized to receive SIRT but who are not regarded as
eligible for SIRT after the pre-treatment assessment will be switched to the
sorafenib only arm within the palliative treatment group.
SIRT will be administered in 1 or 2 treatment sessions, depending on the
involvement of the liver lobes. The study procedure guide will contain further
instructions on the dosing of SIR-Spheres and the treatment procedure.

Sorafenib (curative and palliative arm)
As adjuvant treatment 400mg BID versus placebo, in the curative setting
as well as in the palliatieve setting sorafenib 400mg BID.

RFA (for the curative arm
A maximum of 2 percutaneous RFA sessions (maximum of 2 weeks apart) is
permitted per patient with a maximum of 2 liver lesions treated in each RFA
session. Randomization to sorafenib or placebo is performed after completion of
RFA.
Percutaneous RFA is to be performed according to the manufacturer*s
instructions and following as far as possible routine procedures of the
participating hospital. Applicators should be selected according to the size,
location, and configuration of the lesion(s) to be treated. Typically, RFA will
be performed under conscious sedation, general anesthesia is permitted. After
local anesthesia of the site of puncture, the applicator is positioned in the
center of the lesion using ultrasound-, CT- or MR-guidance. The success of
ablation is to be controlled directly after RFA using ultrasound (preferably
contrast-enhanced ultrasound), contrast-enhanced CT, or MR imaging. If for any
reason RFA is deemed incomplete within the immediate follow-up (up to 2 weeks
after the initial ablation), RFA is to be repeated once (in this case, the
total (maximum) number of RFA sessions will be three).
The study procedure guide will contain further instructions for RFA.

The expected side-effect profiles of sorafenib, SIR-Sphere therapy, and the MR
contrast agent Primovist® are summarized in the study protocol section
8.7.2.4. Overall, the benefit-risk ratio of the SORAMIC trial is regarded as
positive and acceptable.

Local ablation group. This study includes patients with early and advanced
HCC. Patients with early HCC (up to 4 liver lesions of a maximum of 5 cm each)
will be assigned to the local ablation group. In this treatment group,
patients will receive local ablation therapy followed by sorafenib or placebo.
Local ablation therapy with RFA represents an accepted treatment option and
does not constitute a deviation from routine clinical care. The addition of
sorafenib as an adjuvant treatment after local ablation (as planned in this
study in half of the patients assigned to the local ablation group) is
currently not part of clinical care. Sorafenib treatment in these patients is
expected to be associated with adverse events comparable to published data (the
incidence of treatment-related adverse events was 80% in the sorafenib arm in
the SHARP trial, compared to 52% in the placebo arm, see [26]). In the SHARP
trial, adverse events that were more common in the sorafenib arm than in the
placebo arm (e.g., diarrhea, weight loss, and hand*foot skin reaction) were
mainly mild to moderate in severity. The two most relevant grade 3
drug-related adverse events were diarrhea and hand-foot skin reaction (both of
which occurred in 8% of patients in the sorafenib arm). The overall incidence
of serious adverse events from any cause was similar in the two study arms: 52%
(153 patients) in the sorafenib arm and 54% (164 patients) in the placebo arm
[27].

In case of adverse events, the sorafenib dose can be reduced in this study
according to the scheme outlined in the study protocol section 5.5.1. The
expected rate and intensity of adverse events is regarded as acceptable because
sorafenib is expected to exhibit anti-tumor efficacy and to prolong
time-to-recurrence after local ablation therapy. The SORAMIC trial design is
expected to provide relevant data regarding the treatment efficacy of sorafenib
in the adjuvant situation. Patients of the local ablation group who receive
sorafenib may have a personal benefit from participation in this trial. Given
the potential beneficial adjuvant treatment effect of sorafenib and the
potential personal benefit of participating patients, the benefit-risk ratio of
the local ablation treatment group is regarded as acceptable and positive.

Patients of this study group may stay in the study at an average of 16 months.
In this case an average of 7 follow up visits and a final visit may be
conducted. These visits consist of the following procedures: laboratory
assessment (blood samples 18mL and optional additional 12.5mL), ECOG
performance status, Quality of life questionnaire and imaging
(contrast-enhanced CT and Primovist-enhanced MRI).

Palliative study group. Patients with advanced HCC who are not eligible for
the local ablation study group, will be subjected to the palliative treatment
group. All patients in this group will receive sorafenib. Sorafenib has been
approved for the treatment of hepatocellular cancer and is the standard of care
in advanced HCC (see also [28]). The administration of sorafenib in the
palliative group of this study, therefore, does not represent a deviation from
routine clinical care.

SIR-Spheres therapy is currently not routinely performed in patients with
advanced HCC. Half of the patients included in the palliative study group will
be randomized to SIR-Spheres therapy before start of sorafenib treatment.
These patients may suffer adverse events from the application of SIR-Spheres
and from the combined effects of SIR-Spheres and sorafenib.

Current knowledge about the frequency and the severity of adverse events after
SIR-Spheres treatment is summarized in section 8.7.2.4. In this study,
SIR-Spheres treatment will be adapted to the total tumor load of the liver to
reduce the probability of adverse events (see Table 5 in the study protocol
section 5.5.3). Treatment of the whole liver in one session will not be
allowed, two separate lobar treatment sessions are required in the case that
the whole liver needs to be treated. This careful sequential approach of
SIR-Spheres therapy for patients requiring whole liver treatment is expected to
significantly reduce the frequency of adverse events. In addition, the DSMB
will carefully assess the course of the first patients receiving SIRT in the
palliative treatment group. To protect patients participating in this study,
the DSMB may recommend changes in the timing of the start of sorafenib
treatment (e.g., start of sorafenib treatment later than 3 days after the last
SIRT session), or may even recommend to stop this study arm because of adverse
events (see study protocol section 8.9, *stopping rule*).

Patients receiving SIRT in the palliative treatment group are expected to have
personal benefit and a longer overall survival than patients in the
sorafenib-only arm. Considering the expected survival benefit and the measures
planned to reduce the probability for severe and serious adverse events (incl.
installation of a DSMB), the benefit risk ratio of the palliative study group
is regarded as acceptable and positive.

Patients of this study group may stay in the study at an average of 13 months.
In this case an average of 6 follow up visits may be conducted. These visits
consist of the following procedures: laboratory assessment (blood samples 18mL
and optional additional 12.5mL), ECOG performance status and Quality of life
questionnaire. Imaging in this study group is in discretion of the investigator
and will include contrast-enhanced CT and Primovist-enhanced MRI.

Diagnostic Sub-Study. All patients will undergo contrast-enhanced CT and
Primovist-enhanced MRI before being assigned to the local ablation or
palliative study group. Patients of the local ablation study group will be
followed up with contrast-enhanced CT and Primovist-enhanced MRI at 2-months
intervals until recurrence. Contrast-enhanced CT for treatment selection and
follow-up in HCC is regarded as standard of care. Primovist-enhanced MRI is an
additional diagnostic procedure in the context of this clinical study. There
are very few risks associated with MRI scans. The changing radiofrequencies
and magnetic fields theoretically can produce heat, but this is not known to be
associated with relevant side effects. The risk of the injection of MR
contrast agents is considered to be low. Patients with an increased risk of
Primovist-associated adverse events are not allowed to enter this study (e.g.,
patients with a history of allergic reactions, patients with severe renal
dysfunction).

Patients participating in this trial may have a personal benefit from
Primovist-enhanced MRI (more accurate assessment of disease, earlier detection
of tumor recurrence). Considering the potential personal benefit and the low
probability for severe and serious adverse events, the benefit risk ratio of
the diagnostic sub-study is regarded as acceptable and positive.