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

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 05/2008; 26(13):2147-54. DOI: 10.1200/JCO.2007.15.0532
Source: PubMed


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 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.
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).
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.

Full-text preview

Available from:
  • Source
    • "This may have important therapeutic implications since a toxin-conjugated PSMA-targeted mAb could be an effective combination therapy with antiandrogens. Indeed, J591 has been adapted for radioimmunotherapy, and Ab-drug conjugates and therapeutic doses are well tolerated in patients [34, 35]. A well-known Food and Drug Administration (FDA) approved that agent targeting PSMA is capromab pendetide (ProstaScint) [36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.
    Full-text · Article · Oct 2013 · BioMed Research International
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the past two decades, monoclonal antibodies have become one of the important therapeutic modalities for the treatment of cancer. Antibody engineering has immensely contributed to the development of antibody-based cancer therapy. The use of recombinant DNA technology has aided the molecular engineering of antibodies in various ways to improve their efficacy, and to counter various challenges posed in the rational designing of high-impact therapeutics for the treatment of a wide spectrum of malignancies. Such engineering of antibodies has been possible mainly due to their inherent plastic and multidomain structure, which makes it amenable to various modifications. This review highlights the advances in the field of antibody engineering which have enabled the use of antibodies for cancer immunotherapy.
    Preview · Article · Jun 2009 · Current science
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Anticancer drugs are often nonselective antiproliferative agents (cytotoxins) that preferentially kill dividing cells by attacking their DNA at some level. The lack of selectivity results in significant toxicity to noncancerous proliferating cells. These toxicities along with drug resistance exhibited by the solid tumors are major therapy limiting factors that result into poor prognosis for patients. Prodrug and conjugate design involves the synthesis of inactive drug derivatives that are converted to an active form inside the body and preferably at the site of action. Classical prodrug and conjugate design have focused on the development of prodrugs that can overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs. The recent targeted prodrug and conjugate design, on the other hand, hinge on the selective delivery of anticancer agents to tumor tissues thereby avoiding their cytotoxic effects on noncancerous cells. Targeting strategies have attempted to take advantage of low extracellular pH, elevated enzymes in tumor tissues, the hypoxic environment inside the tumor core, and tumor-specific antigens expressed on tumor cell surfaces. The present review highlights recent trends in prodrug and conjugate rationale and design for cancer treatment. The various approaches that are currently being explored are critically analyzed and a comparative account of the advantages and disadvantages associated with each approach is presented.
    Full-text · Article · Feb 2008 · Current Medicinal Chemistry
Show more