Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors

• Published in: Clinical cancer research 2006-07, Vol.12 (13), p.4004-4010
• Main Authors: Hauck, Marlene L, LaRue, Susan M, Petros, William P, Poulson, Jean M, Yu, Daohai, Spasojevic, Ivan, Pruitt, Amy F, Klein, Allison, Case, Beth, Thrall, Donald E, Needham, David, Dewhirst, Mark W
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; canine; Carcinoma - therapy; Carcinoma - veterinary; Combined Modality Therapy; Dog Diseases - therapy; Dogs; Dose-Response Relationship, Drug; doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Doxorubicin - pharmacokinetics; Drug Administration Schedule; Drug Delivery Systems; drug-delivery; Female; hyperthermia; Hyperthermia, Induced - methods; Liposomes; Male; Maximum Tolerated Dose; Microwaves - therapeutic use; Sarcoma - therapy; Sarcoma - veterinary; Temperature; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0226

Purpose: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. Experimental Design: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. Results: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received ≥2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 ± 6.17 ng/mg tissue. Conclusion: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.