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


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/m(2) (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/m(2) (both patients were able to resume therapy at 225 mg/m(2)). The recommended dose for efficacy studies was 225 mg/m(2), 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/m(2), the mean area under the concentration-time profiles of L-377202, Leu-Dox, and Dox were 6 micromol x L/h, 4 micromol x L/h, and 1 micromol x L/h, and peak concentrations were 14 micromol/L, 5 micromol/L, and 120 nmol/L, respectively. At 225 and 315 mg/m(2), 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/m(2).


CONCLUSIONS
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.
DiPaola
Robert S
RS
Department of Medicine, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick 08901, USA. dipaolrs@umdnj.edu
Rinehart
John
J
Nemunaitis
John
J
Ebbinghaus
Scott
S
Rubin
Eric
E
Capanna
Terry
T
Ciardella
Marie
M
Doyle-Lindrud
Susan
S
Goodwin
Susan
S
Fontaine
Michelle
M
Adams
Ned
N
Williams
Adrienne
A
Schwartz
Michael
M
Winchell
Greg
G
Wickersham
Karen
K
Deutsch
Paul
P
Yao
Siu-Long
SL
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C416722:L 377202; D009842:Oligopeptides; D011355:Prodrugs; D004317:Doxorubicin; D017430:Prostate-Specific Antigen