A Phase III Clinical Trial of Intra-arterial TheraSphere® in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (HCC).

According to the international Agency for Research on Cancer (IARC), primary
liver cancer is a major health problem worldwide.
Globally, it is the sixth most commonly diagnosed cancer, with more than
749,000 new cases in 20011. It is the third leading cause of cancer death in
men and sixth among women. In North America and Western or Northern Europe,
areas with historically low rates, the
incidence of liver cancer is increasing, possibly due to increased prevalence
of hepatitis C.

In 2007, the FDA approved sorafenib tosylate (Nexavar®), a small molecule Raf
kinase and VEGF receptor
kinase inhibitor, for the treatment of patients with unresectable
hepatocellular carcinoma (HCC).
The approval was based on the results of an international, multicenter,
randomized, double-blind,
placebo-controlled trial (SHARP trial) in patients with unresectable,
biopsy-proven hepatocellular
carcinoma.

Sorafenib is the standard-of-care (SOC) therapy for patients with advanced
HCC, guidelines recommend the use of sorafenib in this cohort of patient. One
such guideline, the Barcelona Clinic Liver Cancer (BCLC) classification system
recommends use of sorafenib in patient with a classification of stage C HCC.

Moreover, s orafenib is included in the NCCN Clinical Practice Guidelines in
Oncology (NCCN- Hepatobiliary cancersV.1.2010 - HCC5) as one of the possible
treatments for patients with unresectable HCC and extensive liver disease who
are not candidates for transplantation.

Although sorafenib is a SOC in the treatment of patients with HCC, it is
associated with only a modest improvement in median survival as compared to
best supportive care. Further, sorafenib treatment is
associated with significant toxicity. Salem et al recently published their
long-term experience of TheraSphere in the treatment of patients
with HCC.Hilgard et al report treatment of 108 consecutive patients with
advanced HCC using TheraSphere.
At the International Liver Cancer Association conference in September 2010,
Metrakos et al reported
preliminary results of a Phase II investigation of the safety, tolerability and
efficacy of administering
TheraSphere and Nexavar (sorafenib) treatment in patients with HCC.
As illustrated by these published reports, there is now an extensive clinical
experience demonstrating the safety of TheraSphere in the management of
patients with unresectable HCC.

In this trial (STOP-HCC), all patients with unresectable HCC eligible for
treatment with SOC sorafenib may be
considered for study participation. Patients who meet the entry criteria will
be randomized to either the
patient*s planned SOC sorafenib therapy (Control group), or to TheraSphere
administered prior to the
patient*s SOC sorafenib therapy (Treatment group). The primary outcome measure
for this trial is overall
survival.

Our outcome assumption in the Control group is based on the SHARP trial, with a
median overall survival
of 10.7 months for patients treated with sorafenib. We assume a median overall
survival of 15 months in
the Treatment group, (hazard ratio = 0.71). However, due to uncertainty in the
expected treatment
effect, a sample size re-estimation is planned, which would allow the sample
size to increase in order to
detect a smaller increase in median OS time, from 10.7 months in the sorafenib
arm to 14.0 months in the TheraSphere arm (ie, hazard ratio = 0.76).

The objective of the study is to evaluate TheraSphere in the treatment of
patients with unresectable
hepatocellular carcinoma in whom treatment with standard-of-care sorafenib
therapy is planned.

This study is an open-label, prospective, multi-center, randomized clinical
trial.

The Control group will receive planned standard-of-care therapy sorafenib in
accordance with the approved product labeling.
The Treatment group will receive TheraSphere prior to the initiation of
standard-of-care sorafenib treatment. All liver tumors observed at baseline
that are amenable to treatment with TheraSphere should be treated with
TheraSphere prior to the initiation of treatment with sorafenib. In cases where
disease progression amenable to treatment with TheraSphere is observed after
sorafenib treatment has been initiated, TheraSphere should be administered in a
sorafenib treatment window.

An overview of all study visits and related study procedures can be found in
section 3 of the protocol (pages 16-17). A complete description of the study
visits and procedures can be found in section 9 of the protocol (pages 25-39).
Please see summary below:
Screening Period
The following screening and enrollment evaluations should be performed within
14 days prior to randomization:
• ICF (before any study required tests are performed),
• Physical examination,
. Medical history,
• Child-Pugh assessment of chronic liver disease
• Assessment of liver function, including presence/absence of portal
hypertension and normal/abnormal bilirubin levels
• ECOG Performance Status assessment
• Triple phase spiral CT/MRI to assess liver tumor presentation, estimate tumor
burden in the liver.
• Chest CT/MRI to rule out extra-hepatic metastases
• FACT-Hep quality of life questionnaire
• Required laboratory blood work plus α-feto protein (AFP)
Randomization
Upon meeting eligibility for study participation in accordance with the
Eligibility criteria, patients will be randomized 1:1 between the Treatment and
Control groups.
In order to balance the treatment groups, patients will be stratified at
randomization on the basis of Region (North America and Europe vs Asia), ECOG
Performance Status (0 vs 1), presence or absence of branch portal vein
thrombosis.
Control Group (Sorafenib)
All patients randomized to the Control group should start their planned
standard-of-care treatment with sorafenib as soon as possible after
randomization.
Patients will follow standard dosing for sorafenib according to the product
label information as prescribed by the investigator. Medically appropriate dose
adjustments and drug holidays due to adverse events and toxicity are allowable.
Treatment Group (TheraSphere followed by Sorafenib)
As soon as possible after randomization, hepatic angiography will be performed
to assess hepatic vascular anatomy and tumor hypervascularity, followed by a
99mTc-MAA scan to rule-out gastrointestinal flow or unacceptable lung shunting.
Embolization may be performed, if necessary, to close off gastrointestinal flow
so that the patient can qualify for treatment with TheraSphere. The lobe with
the highest tumor burden should be scheduled for first treatment with
TheraSphere.
Patients will not be able to receive TheraSphere if the potential radiation
dose to the lungs exceeds 30 Gy for a single treatment or cumulative 50 Gy or
embolization cannot be performed to effectively block GI blood flow from the
hepatic arterial system. If radiation exposure to the lungs exceeds 30 Gy (or
50 Gy cumulative), dose reduction of TheraSphere is permitted (minimum dose
allowed is 90 Gy ± 10%).
If after consideration of dose reduction, radiation exposure to the lung
continues to be greater than 30 Gy (or 50 Gy cumulative), sorafenib treatment
will be initiated as soon as possible and 99mTc-MAA will be repeated after 4
weeks of continuous treatment with sorafenib. If radiation exposure to the lung
is less than 30Gy for a single treatment or 50Gy cumulative within a target
dose of 90-120 Gy +10% , the patient may commence treatment with TheraSphere.
In such instances, sorafenib should be discontinued at least 7 days prior to
the administration of TheraSphere and resume sorafenib at least 2 weeks after
the administration of TheraSphere. If radiation exposure to the lung is outside
of the permitted range, treatment with sorafenib should be continued.
In the case where TheraSphere could not be delivered at at target dose of 120
Gy ± 10% within 28 days of randomization, these patients will be included in
the Treatment Group Intent-to-Treat analysis, but not in the Treatment Group
Per-Protocol analysis.

TheraSphere Treatment #1: TheraSphere treatment should occur within 28 days of
randomization, and prior to the initiation of sorafenib. The number of
infusions required to achieve lobar treatment will be determined by the
Investigator, based on the hepatic vascular anatomy.
Patients will receive 120 Gy ± 10% of TheraSphere to the treated lobe of the
liver and may be administered in multiple infusions to address vascular
abnormalities.
TheraSphere Treatment #2: Patients who have bilobar disease at randomization
should have TheraSphere administered to the untreated lobe. If needed, a second
angiogram and/or 99mTc-MAA scan should be performed. Such treatments typically
take place 28 days after the treatment to the first lobe.
From 2 to 6 weeks following TheraSphere treatment of all treatable liver tumors
observed at the time of randomization, patients should initiate
standard-of-care sorafenib treatment in accordance with the sorafenib label
directions.
Re-treatment of the same patient with further cycles of TheraSphere is
permitted if a treatable progression is detected during follow-up evaluations.
Any re-treatment should take place a minimum of 28 days from the last
TheraSphere treatment administered to that lobe. A maximum of 2 re-treatments
are permitted in any patient.

Study Visits and Follow up
Screening evaluations should be completed within 14 days prior to randomization.
For patients randomized to sorafenib, study visits will take place every 8
weeks for as long as the patient remains on the trial. Additional visits may be
scheduled as needed when initiating sorafenib treatment, and to manage any
adverse events and adjustments to sorafenib dosing.
For Patients randomized to TheraSphere, the pre-treatment evaluations and
TheraSphere treatment to the first lobe should take place during the first 3 to
4 weeks following randomization. For patients with bilobar disease, the
evaluations and TheraSphere treatment to the 2nd lobe should take place during
weeks 5 to 8 weeks following randomization. After TheraSphere treatment,
subsequent study visits will take place every 8 weeks from randomization for as
long as the patient remains on the trial.
After start of sorafenib therapy, patients may have additional visits as needed
to adjust sorafenib dosing. Dosing of sorafenib should be consistent with the
relevant label instructions, with allowance for appropriate adjustments based
on the investigators medical judgment.
In general, follow up visits take place approximately every 8 weeks from
randomization until one of the study discontinuation criteria is met (see
9.2.19). The following assessments take place at the follow-up visit:
. ECOG Performance Status assessment
. Standard laboratory blood draw for CBC, differential, electrolytes, BUN,
glucose, liver function test, coagulation panel, and α-fetoprotein biomarker
. Triple phase spiral abdomen CT/MRI scan and spiral CT/MRI scan of chest and
pelvis
. Child-Pugh Status
. QOL questionnaire
. Adverse event reporting