Study of ThermoDox With Standardized Radiofrequency Ablation (RFA) for Treatment of Hepatocellular Carcinoma (HCC)

A Phase III, Randomized, Double Blind, Dummy-Controlled Study of ThermoDox® (Lyso-Thermosensitive Liposomal Doxorubicin-LTLD) in Hepatocellular Carcinoma (HCC) Using Standardized Radiofrequency Ablation (RFA) Treatment Time ≥ 45 Minutes for Solitary Lesions ≥ 3 cm to ≤ 7 cm

The purpose of this study is to determine whether ThermoDox, a thermally sensitive liposomal doxorubicin, is effective in the treatment of non-resectable hepatocellular carcinoma when used in conjunction with standardized radiofrequency ablation (sRFA).

This is a Phase III, randomized, double blind, dummy controlled safety and efficacy study of ThermoDox plus sRFA compared to sRFA plus dummy infusion using standardized treatment dwell time for solitary HCC lesions ≥ 3.0 cm to ≤ 7.0 cm. An sRFA treatment for this protocol is defined as the dwell time of ≥ 45 minutes measured from the first activation of the RFA probe through removal of the RFA probe after the final ablation cycle or deployment.

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 24 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 24 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 24 hours prior to infusion of the study medication, and a dummy infusion 30 minutes prior to dummy infusion of Sodium Chloride 0.9% or 5% Dextrose (D5W). 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 goal is to reach a > 45 minute dwell time which can be achieved by employing at least four ablation cycles or deployments in order to ablate the tumor as well as a 360º 1.0 cm tumor-free margin surrounding the tumor.with an estimated overall procedure time of less than 3 hours.

A subject who has an incomplete ablation is eligible for 1 retreatment procedure within 21 days after the radiological imaging exam showing residual disease at Day 28. Subjects will be retreated only once with the same RFA equipment and treatment assigned at randomization. Subjects with a complete ablation after retreatment will be followed both for PFS and for OS.

If after 2 ablations the subject has local, distant intrahepatic, or extrahepatic HCC, then the subject will be considered a treatment failure and will have met the PFS endpoint. The subject will be followed for OS every 3 months. Among subjects who are not treatment failures, five repeat treatments are permitted to treat a recurrent lesion or to treat newly-identified local or distant intrahepatic lesions at the Investigator's discretion after the PFS endpoint is reported and with agreement from the Sponsor. The subject must be eligible for retreatment consistent with the safety eligibility criteria and will be retreated with the same randomized treatment.

CT or MRI imaging will be used to assess the effectiveness of the ablation therapy. The blind will be maintained at the level of the imaging reads. Investigator determined radiological progression must be observed and recorded prior to beginning alternate treatments for HCC. Posttreatment imaging will be obtained at months 1, 5, 9, 13, 17, 21, 25, then every 6 months (+/- 2 weeks) until radiological progression is seen. 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 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 if clinically indicated and based on the treating physician's medical judgment.

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

Inclusion Criteria:

1. Male or female ≥ 18 years of age.

2. Diagnosed with a single HCC lesion ≥ 3.0 cm but ≤ 7.0 cm in maximum diameter based on diagnosis at screening.

   • Subjects meeting the American Association for the Study of Liver Disease (AASLD) criteria may be randomized without a biopsy, but will undergo a biopsy during the RFA procedure unless contraindicated or unattainable.
   • Subjects not meeting the AASLD criteria for HCC will need a biopsy to confirm HCC prior to randomization.

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

   • The position and accessibility of the target lesion allows for the safe administration of multiple ablation cycles or deployments to achieve a probe dwell time of ≥ 45 minutes.
   • Not a candidate for surgical resection according to the local guidelines for resection and in the Investigator's judgment.

4. Child-Pugh Class A without either current encephalopathy or ascites.

5. Left Ventricular Ejection Fraction (LVEF) ≥ 50%.

6. Eastern Cooperative Oncology Group (ECOG) performance status 0.

7. Willing to sign an informed consent form, indicating awareness of the investigational nature of this study that is in keeping with the policies of the institution.

Exclusion Criteria:

1. Is scheduled for liver transplantation

2. Expected ablation volume > 30% of total liver volume or removal of 3 hepatic segments

3. More than 1 lesion identified during baseline.

4. Have previously received therapeutic treatment for HCC outside the study protocol or is expected to receive concomitant HCC treatment prior to PFS event.

5. 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.

6. Have previously received any anthracycline outside the protocol

7. Have extrahepatic metastasis.

8. Have portal or hepatic vein tumor invasion/thrombosis.

9. Have body temperature >101ºF (38.3ºC) immediately prior to study treatment.

10. Baseline laboratories (repeat lab tests are permitted to evaluate eligibility during the Screening Period. Lab results must be within protocol range prior to study treatment.)

    • Absolute neutrophil count < 1500/mm3
    • Platelet count < 75,000/mm3
    • 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) Note: If clinically indicated, subjects may receive platelets or packed red blood cell (RBC) transfusions and be re-evaluated after condition is treated.

11. Baseline Chemistry

    • Serum creatinine ≥ 2.5 mg/dL or calculated creatinine clearance (CrCl) ≤25.0 mL/min.
    • Serum bilirubin > 3.0 mg/dL.
    • Serum albumin < 2.8 g/dL.

12. Have any known allergic reactions to any of the drugs or liposomal components or intravenous imaging agents that prohibit the ability to complete the imaging requirements.

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

14. Women of childbearing potential and men 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 or men who have undergone a vasectomy must use a second form of birth control).

15. 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.

16. Have contraindications to receiving doxorubicin hydrochloride (HCl).

17. Are being treated with other investigational agents.

18. Use of an investigational drug outside this study within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication.

19. 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.

20. HIV positive.

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

22. Evidence of hemachromatosis.