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A Phase I Dose Escalation Tolerability Study of ThermoDox™ (Thermally Sensitive Liposomal Doxorubicin) in Combination With Radiofrequency Ablation (RFA) of Primary and Metastatic Tumors of the Liver

Phase 1
18 Years
Not Enrolling
Hepatocellular Carcinoma, Liver Neoplasms

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Trial Information

A Phase I Dose Escalation Tolerability Study of ThermoDox™ (Thermally Sensitive Liposomal Doxorubicin) in Combination With Radiofrequency Ablation (RFA) of Primary and Metastatic Tumors of the Liver

Ablative treatment approaches, such as RFA or microwave ablation, have received increased
attention as alternates to other treatment approaches such as hepatic arterial embolization
or chemoembolization (TACE) or percutaneous ethanol injection (PEI) in the majority of
patients who are either not candidates for surgical resection or are not offered palliative
supportive care only for diffuse disease. RFA can be applied repetitively to the same
patient to treat multiple tumors at time of diagnosis or upon tumor recurrence (local or
distant to the site of ablation), and is largely limited in its application only by tumor
location and size (tumors near larger vessels, bowel or the hepatobiliary tree are more
difficult to ablate). To extend the volume of the ablation region in a controlled fashion
in patients and to improve the ability to kill tumor cells in the ablation margin region and
allow for the improved treatment of HCC and MLC lesions > 3 cm in diameter by complete
thermal ablation, Celsion Corporation has developed ThermoDox, a thermally sensitive,
intravenously administered liposomal formulation of doxorubicin capable of selectively
releasing its drug contents when exposed to temperatures of > 39.5°C. The concept behind
this treatment approach is to create a large concentration gradient of doxorubicin in the
immediate region of the tumor which borders the zone of RFA induced cell necrosis. The
temperature isotherms produced in this boundary region should be adequate to activate
doxorubicin release by the thermally sensitive liposomes deposited locally around the
ablation zone. This in effect increases the region of tissue that can be treated beyond
that achievable by RFA alone. Several clinical objectives are being tested in this study.
The MTD for ThermoDox is to be confirmed. This study will assess the safety of using
ThermoDox in conjunction with RFA over multiple cycles, consistent with the clinical needs
of the subjects. While this study is not powered to define effectiveness of the combination
of RFA plus ThermoDox, the results of this study should allow for an assessment of risk and
benefit for designing future studies. This study will also test alternative infusion
reaction prophylaxis regimens.

Inclusion Criteria:

- Be 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

- Have a diagnosis of metastatic liver cancer (MLC) or primary hepatocellular cancer
(HCC) confined to the liver.

- Be an appropriate candidate for receiving RFA as a medically indicated treatment.

- Have an echocardiogram revealing an Ejection Fraction (EF) ≥ 50%.

- Willing to return to the study site for their imaging scans.

- Have life expectancy of ≥ 3 months.

- Have ECOG performance status of 0-2 or Karnofsky score of 60-100% (see Appendix II).

- Have no more than Childs-Pugh Class B liver disease.

- Subjects must have no prior doxorubicin exposure.

- No single lesion should be > 7 cm in maximum diameter.

- Subjects must agree to receive no other systemic therapy from the time of study
enrollment until a minimum of 21 days after their ThermoDox infusion

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.

- Are pregnant or breast feeding. In women of childbearing potential, a negative
pregnancy test (serum) is required at baseline, 1 month and each 3 month follow-up

- Are not practicing an acceptable form of birth control (i.e. diaphragm, cervical cap,
condom, surgical sterility or birth control pills. Woman whose husband has undergone
a vasectomy must use a second form of birth control).

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

- Have portal or hepatic vein invasion/thrombosis.

- Have PT or PTT > 1.5 times the institution's upper normal limit (UNL), except in
subjects who are therapeutically anticoagulated for non-related medical conditions
such as atrial fibrillation.

- Have platelet count > 75,000/mm3, absolute neutrophil count > 1500/mm3, or Hgb > 10
(unless the hemoglobin value has been stable, the subject is cardiovascularly stable,
asymptomatic and judged able to withstand the RFA

- Have serum creatinine ≤ 2.0 mg/dl (or calculated CrCl ≤ 60mL/min).

- Have contraindications to receiving doxorubicin HCl.

- Are being treated with other investigational agents (within a minimum of 30 days or 5
half-lives of the investigational agent).

- Have other concurrent malignancy (subjects with benign or non aggressive malignant
tumors-e.g.: squamous cell cancer 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 cardiovascular disease or LVEF < 50%.

- Evidence of hemachromatosis.

- Are on any of the medications listed in section 6.3, which could have an adverse
effect when combined with the study drug, and who cannot stop the medication for the
duration of the study and 30 days beyond the treatment.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the maximum tolerated dose (MTD) of systemically delivered, heat-activated liposome encapsulated doxorubicin (ThermoDox) in combination with radiofrequency ablation (RFA) of liver neoplasms.

Outcome Time Frame:

1 month

Safety Issue:



United States: Food and Drug Administration

Study ID:




Start Date:

February 2007

Completion Date:

December 2009

Related Keywords:

  • Hepatocellular Carcinoma
  • Liver Neoplasms
  • Radiofrequency ablation
  • RFA
  • Doxorubicin
  • Liposome
  • HCC
  • MLC
  • hepatocellular carcinoma
  • liver tumor
  • tumor
  • ablation
  • heat therapy
  • anti-tumor
  • liver cancer
  • metastatic liver cancer (MLC)
  • Neoplasms
  • Carcinoma
  • Liver Neoplasms
  • Neoplasm Metastasis
  • Carcinoma, Hepatocellular



Northshore Hospital - Long Island Jewish Health System Manhasset, New York  11030