Originally published as JCO Early Release 10.1200/JCO.2007.15.0532 on March 24 2008

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Galsky, M. D. Articles by Scher, H. I. Search for Related Content PubMed PubMed Citation Articles by Galsky, M. D. Articles by Scher, H. I. Social Bookmarking                            What's this?

Phase I Trial of the Prostate-Specific Membrane Antigen–Directed Immunoconjugate MLN2704 in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer

Matthew D. Galsky, Mario Eisenberger, Sandra Moore-Cooper, W. Kevin Kelly, Susan F. Slovin, Anthony DeLaCruz, Yih Lee, Iain J. Webb, Howard I. Scher

From the Genitourinary Oncology Service, Department of Medicine, and Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; Johns Hopkins Medical Institutions, Baltimore, MD; and Millennium Pharmaceuticals Inc, Cambridge, MA

Corresponding author: Howard I. Scher, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: scherh{at}mskcc.org

Purpose MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)–expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti–prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704.

Patients and Methods Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed.

Results Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m². Eighteen of these patients received three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug–related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m². Two (22%) of the nine patients treated at 264 or 343 mg/m² had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m².

Conclusion Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.

published online ahead of print at www.jco.org on March 24, 2008.

Supported in part by Millennium Pharmaceuticals Inc.

Presented in part at the Prostate Cancer Symposium of the American Society of Clinical Oncology, February 17-19, 2005, Orlando, FL, and at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?