Characterization of a novel prostate-specific antigen-activated peptide-doxorubicin conjugate in patients with prostate cancer

Purpose: To evaluate safety and pharmacokinetics (PK), and determine the recommended dose for efficacy studies, of L-377202, a novel peptide conjugate of doxorubicin (Dox) that releases the active metabolites leucine-doxorubicin (Leu-Dox) and Dox on cleavage by membrane-bound prostate-specific antigen (PSA). Patients and Methods: Nineteen patients with advanced hormone-refractory prostate cancer were treated intravenously with 71 cycles of L-377202 at escalating dose levels of 20 (n = 1), 40 (n = 3), 80 (n = 4), 160 (n = 3), 225 (n = 6), and 315 mg/m² (n = 2) once every 3 weeks. Toxicity, response, and PK of L-377202 were assessed. Results: L-377202 was well tolerated. Dose-limiting grade 4 neutropenia was noted in two of two patients administered 315 mg/m² (both patients were able to resume therapy at 225 mg/m²). The recommended dose for efficacy studies was 225 mg/m², which induced grade 4 neutropenia in one of six patients. PK studies demonstrated that L-377202 was metabolized to Leu-Dox and Dox. PK were linear; after administration of single doses of 225 mg/m², the mean area under the concentration-time profiles of L-377202, Leu Dox, and Dox were 6 μmol·L/h, 4 μmol·L/h, and 1 μmol·L/h, and peak concentrations were 14 μmol/L, 5 μmol/L ttmol/L, and 120 nmol/L, respectively. At 225 and 315 mg/m², five patients completed at least three cycles of therapy; two patients had a greater than 75% decrease in PSA, and one patient had a stabilized PSA. No response was noted at dose levels less than 225 mg/m². Conclusion: This is the first study of selective drug delivery in humans using a novel PSA-activated agent. L-377202 was cleaved to produce detectable levels of the active metabolites Leu-Dox and Dox. L-377202 was well tolerated and established a safe dose level for further study.