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


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/m(2). Eighteen of these patients received >or= 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/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) 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/m(2).


CONCLUSIONS
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.
Galsky
Matthew D
MD
Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Eisenberger
Mario
M
Moore-Cooper
Sandra
S
Kelly
W Kevin
WK
Slovin
Susan F
SF
DeLaCruz
Anthony
A
Lee
Yih
Y
Webb
Iain J
IJ
Scher
Howard I
HI
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000276:immunology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure; D016896:Treatment Outcome
D000726:Androgen Antagonists; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D018796:Immunoconjugates; C528898:MLN2704 antibody; D008453:Maytansine; D013739:Testosterone; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II