Phase 3 Study of ThermoDox With Radiofrequency Ablation (RFA) in Treatment of Hepatocellular Carcinoma (HCC)

This will be a Phase III, randomized, double-blinded, dummy-controlled, efficacy, and safety
study of ThermoDox plus RFA versus RFA plus dummy infusion.

The 50 mg/m2 ThermoDox or dummy infusion will be administered IV over 30 minutes. As part of
blinded pre-medication ThermoDox treated subjects will receive 20 mg of dexamethasone orally
48 hours prior to the drug infusion for infusion reaction prophylaxis. Subjects on the
control arm will receive a matching dummy pre-medication pill orally at 48 hours prior to
infusion of the study treatment. Thirty minutes prior to receiving the ThermoDox infusion,
subjects will receive a blinded dose of 20 mg of IV dexamethasone, 50 mg IV diphenhydramine
and either 50 mg of IV ranitidine or 20 mg of IV famotidine. Subjects on the control arm
will receive a masked dummy pre-medication pill orally at 48 hours prior to infusion of the
study medication, and a dummy infusion 30 minutes prior to dummy infusion of D5W (250 cc of
5% Dextrose solution). RFA will be initiated approximately at a minimum of 15 minutes after
the initiation of study drug infusion and should be completed no later than 3 hours after
study drug infusion initiation. The total length of the RFA procedure is proportional to the
size of the tumor(s) involved and is anticipated to range from 12 to 60 minutes for each
lesion with an estimated overall procedure time of less than 3 hours.

Subjects with incomplete ablations will be re-treated to complete the ablation according to
the treatment assigned at randomization. The completion of an ablation in this manner will
restart the timeline of the study-related visits/procedures. This repeated ablation
procedure cannot occur earlier than 21 days post-ablation but no later than 14 days after
the first post-ablation CT scan assessment. These subjects will start over at screening (see
Table 1). If a complete ablation is not achieved after these two study treatments, the
subject will be considered a treatment failure and the patient will be discontinued and
followed for survival only.

Subjects who recur with local and/or distant intrahepatic HCC after a complete initial
ablation will have met the primary endpoint of progression-free survival. However, if these
subjects have lesions that are amenable to RFA the standard of care is to consider them for
repeat RFA. Therefore, these subjects may receive treatment to which they were randomized if
they continue to meet the inclusion and exclusion criteria of the protocol. Subjects who
develop any extrahepatic lesion will have met the primary endpoint and will be discontinued
from study treatment but will still be followed for overall survival.

Dynamic Contrast CT imaging will be used to assess the effectiveness of the ablation
therapy. The blind will be maintained at the level of CT scan reads. All protocol-specified
CT images will be centrally read and assessed by the endpoint committee in a blinded
fashion. Posttreatment CT scans will be obtained at months 1, 3, 5, 7, 9 and 12 and every
three months thereafter until withdrawal. Adverse event assessments and laboratory
examinations will occur at each visit. All subjects will be monitored throughout the
investigational period.

Patients that meet inclusion/exclusion criteria may be at risk for contrast-induced
nephropathy (CIN) when undergoing the required CT with contrast procedures. The
investigators must be mindful of the risk factors (e.g. diabetes, borderline renal function)
associated with CIN and employ strategies to reduce the risk of CIN. In subjects with
diabetes or borderline renal function (creatinine greater than 1.5 mg/dL) special
precautions (e.g. hydration, contrast dose reduction, follow up creatinine determination)
should be employed. An accepted procedure is adequate intravenous volume expansion with
isotonic saline (1.0 - 1.5 mL/kg per hour) for 3-12 hours before the procedure and continued
for 6-24 hours.

All randomized subjects will be followed for safety and overall survival.

Inclusion Criteria:

- Diagnosed hepatocellular carcinoma (HCC)

- No more than 4 HCC lesions with at least one ≥ 3.0 cm and none > 7.0 cm in maximum
diameter, based on diagnosis at screening.

- If a subject has a large lesion (5.0 - 7.0 cm), any other lesions must be less than
5.0 cm.

- Anticipated ablation volume will be no larger than either removal of 3 hepatic
segments or removal of more than 30% of total liver volume (as per maximum surgical
limit).

- If additional lesions are discovered during the laparoscopic or open treatment
procedure, that were undetectable by CT at screening, the size and location of the
lesion(s) will be recorded in the CRF and the lesions will be treated at the
discretion of the physician and guided by the local standard of care. The subject
will remain on study if all lesions are treated. If any lesions cannot be completely
ablated within two treatment attempts the subject will be considered a treatment
failure.

- Study subjects being considered for re-treatment after disease progression may have
more than 4 lesions.

- Male or female 18 years of age or older.

- Are willing to sign an informed consent form, indicating that they are aware of the
investigational nature of this study that is in keeping with the policies of the
institution.

- Be an appropriate candidate for receiving RFA as a medically indicated treatment as
evaluated by the following factors:

- Number of lesions

- Size of lesions

- Overall health of liver

- Not a candidate for surgical resection

- Have an echocardiogram revealing a Left Ventricular Ejection Fraction (LVEF) ≥ 50%.
Measurements with a multiple gated acquisition (MUGA) scan are allowed if an
echocardiogram cannot be performed. The same method of measurement should be used to
evaluate ejection fraction (EF) of the subject for the duration of the study.

- Willing to return to the study site for their study visits.

- Have life expectancy of ≥ 4 months.

- Have Child-Pugh Class A or B liver disease without encephalopathy or/and ascites.

Exclusion Criteria:

- Have serious medical illnesses including, but not limited to, congestive heart
failure, myocardial infarction or cerebral vascular accident within the last six
months, or life threatening cardiac arrhythmias.

- Is scheduled for liver transplantation.

- Have previously received any treatment for HCC (except for study subjects being
considered for completion of treatment or re-treatment).

- Have previously received any doxorubicin (study subjects being considered for
completion of treatment or re-treatment may have received ThermoDox previously).

- Have extrahepatic metastasis.

- Are pregnant or breast-feeding. In women of childbearing potential, a negative
pregnancy test (serum) is required prior to study treatment.

- Women of childbearing potential who are not practicing an acceptable form of birth
control (i.e. diaphragm, cervical cap, condom, surgical sterility or birth control
pills. Women whose partner has undergone a vasectomy must use a second form of birth
control).

- Have any known allergic reactions to any of the drugs or liposomal components or
intravenous imaging agents to be used in this study.

- Have portal or hepatic vein tumor invasion/thrombosis.

- Have INR > 1.5 times the institution's upper normal limit (UNL), except in subjects
who are therapeutically anticoagulated for medical conditions unrelated to HCC such
as atrial fibrillation. Subjects may be re-screened after condition is treated or
anticoagulant is withheld.

- Have platelet count < 75,000/mm3, absolute neutrophil count < 1500/mm3, or Hgb < 10.0
g/dL (unless the hemoglobin value has been stable, the subject is cardiovascularly
stable, asymptomatic and judged able to withstand the RFA procedure).

- Have serum creatinine ≥ 2.5 mg/dL or calculated creatinine clearance (CrCl) ≤ 25.0
mL/min.

- Have serum bilirubin > 3.0 mg/dL.

- Have serum albumin < 2.8 g/dL.

- Have body temperature >1010F (38.30C) immediately prior to study treatment.

- Have contraindications to receiving doxorubicin HCl.

- Are being treated with other investigational agents.

- Use of an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of study medication (study subjects being considered for
completion of treatment or re-treatment may have received ThermoDox previously).

- Have other concurrent malignancy (subjects with treated squamous cell carcinoma of
the skin or basal cell carcinoma of the skin may be included), evidence of
extrahepatic cancer from their primary malignancy, or ongoing, medically significant
active infection.

- Documented HIV positive.

- NYHA class III or IV functional classification for heart failure.

- Evidence of hemachromatosis.

- Have history of contrast-induced nephropathy.