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.