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Characterization of a Novel Prostate-Specific Antigen–Activated Peptide-Doxorubicin Conjugate in Patients With Prostate Cancer

From the Department of Medicine, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, and The Cancer Institute of New Jersey and the Dean and Betty Gallo Prostate Cancer Center, New Brunswick; Merck Research Laboratories, Rahway, NJ; University of Alabama Comprehensive Cancer Center, Birmingham, AL; US Oncology, Inc, Dallas, TX; and Merck Research Laboratories, West Point, PA.

Address reprint requests to Robert S. DiPaola, MD, The Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901; email: dipaolrs{at}umdnj.edu

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, 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.

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