Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer Journal Article

Authors: Galsky, M. D.; Eisenberger, M.; Moore-Cooper, S.; Kelly, W. K.; Slovin, S. F.; Delacruz, A.; Lee, Y.; Webb, I. J.; Scher, H. I.
Article Title: Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer
Abstract: 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. © 2008 by American Society of Clinical Oncology.
Keywords: adult; clinical article; treatment outcome; aged; aged, 80 and over; bone neoplasms; middle aged; bone tumor; treatment failure; unclassified drug; clinical trial; constipation; fatigue; neutropenia; diarrhea; dose response; drug safety; hypertension; liver function; side effect; anorexia; prostate specific antigen; metabolism; metastasis; computer assisted tomography; erythropoietin; anemia; leukopenia; nausea; neuropathy; thrombocytopenia; vomiting; drug administration schedule; tomography, x-ray computed; bone pain; antineoplastic activity; tumor regression; drug resistance; pathology; dose-response relationship, drug; drug resistance, neoplasm; monoclonal antibody; alanine aminotransferase blood level; febrile neutropenia; hyperglycemia; lymphocytopenia; prostate cancer; prostatic neoplasms; membrane antigen; blood; immunology; correlation analysis; immunogenicity; prostate tumor; androgen antagonists; drug clearance; single drug dose; maximum tolerated dose; phase 1 clinical trial; antiandrogen; drug administration; drug dose increase; infusions, intravenous; testosterone; prochlorperazine; intravenous drug administration; glutamate carboxypeptidase ii; glutamate carboxypeptidase ii, human; antigens, surface; body surface; antibody conjugate; immunoconjugates; musculoskeletal pain; monoclonal antibody mln 2704; mln2704 antibody
Journal Title: Journal of Clinical Oncology
Volume: 26
Issue: 13
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2008-05-01
Start Page: 2147
End Page: 2154
Language: English
DOI: 10.1200/jco.2007.15.0532
PUBMED: 18362364
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 24" - "Export Date: 17 November 2011" - "CODEN: JCOND" - "Source: Scopus"
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MSK Authors
  1. Susan Slovin
    184 Slovin
  2. Howard Scher
    816 Scher