title: Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles.
abstract: Doxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60, 60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions.
authors.affiliation: Department of Medicine, Institut Gustave-Roussy, Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Kattan
authors.forename: J P
authors.initials: JP
authors.lastname: Droz
authors.forename: P
authors.initials: P
authors.lastname: Couvreur
authors.forename: J P
authors.initials: JP
authors.lastname: Marino
authors.forename: A
authors.initials: A
authors.lastname: Boutan-Laroze
authors.forename: P
authors.initials: P
authors.lastname: Rougier
authors.forename: P
authors.initials: P
authors.lastname: Brault
authors.forename: H
authors.initials: H
authors.lastname: Vranckx
authors.forename: J M
authors.initials: JM
authors.lastname: Grognet
authors.forename: X
authors.initials: X
authors.lastname: Morge
mesh_terms: D000328:Adult; D000368:Aged; D003487:Cyanoacrylates; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D003487:Cyanoacrylates; D004337:Drug Carriers; C057532:polyisohexylcyanoacrylate; D004317:Doxorubicin