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.