Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.
OBJECTIVE
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.


METHODS
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 > or = 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.


CONCLUSIONS
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.
Hauck
Marlene L
ML
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA. marlene_hauck@ncsu.edu
LaRue
Susan M
SM
Petros
William P
WP
Poulson
Jean M
JM
Yu
Daohai
D
Spasojevic
Ivan
I
Pruitt
Amy F
AF
Klein
Allison
A
Case
Beth
B
Thrall
Donald E
DE
Needham
David
D
Dewhirst
Mark W
MW
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002277:Carcinoma / Q000628:therapy / Q000662:veterinary*; D003131:Combined Modality Therapy; D004283:Dog Diseases / Q000628:therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D005260:Female; D006979:Hyperthermia, Induced / Q000379:methods*; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008872:Microwaves / Q000627:therapeutic use; D012509:Sarcoma / Q000628:therapy / Q000662:veterinary*; D013696:Temperature; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D008081:Liposomes; D004317:Doxorubicin