Phase I Study of Heat-Deployed Liposomal Doxorubicin during Radiofrequency Ablation for Hepatic Malignancies

Abstract

PURPOSE A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD) (Celsion Corp., Columbia, MD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic (PK) properties, and dose limiting toxicity (DLT) of LTLD during this combination therapy. MATERIALS AND METHODS Subjects eligible for percutaneous or surgical RFA with primary (n=9) or metastatic (n=15) tumors of the liver, with lesions 4 or less in number and up to 7 cm in diameter were included. RFA was initiated 15 minutes after starting a 30 minute intravenous LTLD infusion. Dose levels between 20 and 60 mg/m2 were evaluated. MRI, PET and CT scans were performed at predetermined intervals pre and post-treatment until evidence of recurrence, administration of additional antitumor treatment, or a total of 3 years. RESULTS DLT criteria were met at 60 mg/m2, and the MTD was defined as 50 mg/m2. RFA was performed during the peak of the plasma concentration-time curve, in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. CONCLUSION LTLD can be safely administered systemically at the MTD (50 mg/m2) in combination with RFA, with limited and manageable toxicity. Further evaluation of this agent combined with RFA is warranted to determine its role in the management of liver tumors.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…Pegylated liposomes with irinotecan Phase I Recurrent high-grade gliomas [18,197] Recently, new strategies in liposomal research have gained interest, and some clinical trials based on the combination of different chemotherapeutic agents, and stimuli-responsive release approaches, have been started [267,268] This is the case of the phase I/II/III trials with liposomes containing cytarabine and daunorubicin (CPX-351) in the treatment of acute myeloid leukemia [18,[269][270][271], the phase II trials of liposomes containing irinotecan·HCl and floxuridine (CPX-1) as a therapy for advanced colorectal cancer [18,218,272], and the thermosensitive liposomes containing doxorubicin (ThermoDox) in phase III for the treatment of hepatocellular carcinoma [18], and in phase I/II to recurrent chest wall breast cancer, locally recurrent breast cancer, primary and metastatic tumors of the liver, and metastatic colorectal cancer [18,273,274].…”

Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions

“…About 90% of the liposomal doxorubicin plasma area under the curve (AUC 0-¥ ) occurred during the first 3 hours following infusion (19), establishing this period as optimal for RFA. An LTLD þ RFA dose-response relationship (P ¼ 0.04) was found for time to treatment failure, with a median of 80 days for doses <50 mg/m 2 versus 374 days for doses !50 mg/m 2 (20).…”

“…In a phase I liver cancer trial, the MTD of LTLD was found to be 50 mg/m 2 (19). About 90% of the liposomal doxorubicin plasma area under the curve (AUC 0-¥ ) occurred during the first 3 hours following infusion (19), establishing this period as optimal for RFA.…”

Liposomal Doxorubicin Plus Radiofrequency Ablation for Complete Necrosis of a Hepatocellular Carcinoma

“…This timing also maximizes the drug delivered (roughly correlated with the area under the curve on the pharmacokinetic graph) 6 .…”

“…phase i dose-escalation clinical trial of rfa with ltld, a patient underwent transplantation after the combined approach of rfa plus drug 6 . Pathology showed no residual tumour at the treatment site.…”