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Originally published as JCO Early Release 10.1200/JCO.2007.15.0532 on March 24 2008 © 2008 American Society of Clinical Oncology. Phase I Trial of the Prostate-Specific Membrane Antigen–Directed Immunoconjugate MLN2704 in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer
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 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.
Prostate-specific membrane antigen (PSMA), a membrane-bound glycoprotein expressed on surfaces of malignant prostate epithelial cells, is the most restricted prostate cancer–associated antigen defined to date. Expression is increased in high-grade tumors compared with low-grade tumors and is upregulated further after androgen deprivation and in metastases. Antibodies binding to the cell surface are internalized rapidly, making PSMA an ideal target for radiopharmaceutical or cytotoxic antibody conjugates. Its selective expression on prostate cancer cells minimizes the exposure of normal cells to toxins.1-4 Low-level PSMA expression has been demonstrated in the duodenal epithelium and the proximal tubule cells in the kidney; however, these sites are thought to be inaccessible to circulating antibodies.2 Clinical studies with radiolabeled MLN591 (Millennium Pharmaceuticals, Cambridge, MA) or J591, a deimmunized monoclonal antibody directed at an external domain of PSMA, have confirmed selectivity for prostate cancer metastases in bone and soft tissue and demonstrated durable antitumor activity.5-7 MLN2704 is an immunoconjugate designed to deliver the maytansine analog drug maytansinoid-1 (DM1) to PSMA-expressing cells via MLN591. Although maytansine shows activity in a range of tumor types, its therapeutic index is narrow.8 DM1 was developed specifically to enable antibody-directed delivery of a maytansinoid to tumors while avoiding toxicities associated with the unconjugated drug.9 DM1, a microtubule inhibitor, is 100- to 1,000-fold more potent than conventional cytotoxic agents. DM1 conjugates have been explored in various malignancies using different antibodies.10,11 Because antimicrotubule cytotoxic agents have shown activity in prostate cancer, including prolongation of life, they are of particular interest.12,13 MLN2704 binds to PSMA, is rapidly internalized, and thereby delivers DM1 directly to prostate cancer cells. MLN2704 has demonstrated selective antitumor activity in preclinical models. In prostate cancer cell lines, MLN2704 had an inhibitory concentration at 50% (IC50) of 1.4 nmol/L for PSMA-positive LNCaP cells compared with 61.3 nmol/L for PSMA-negative PC3 cells.14 In PSMA-positive CWR22 prostate cancer xenografts, MLN2704 delayed tumor growth significantly more than equivalent doses of DM1 alone (46.4 v 9.5 days, respectively; P = .006).15 MLN2704 showed a favorable safety profile in both mice and cynomolgus monkeys (no PSMA expression in either species16), and one tenth of the highest nonseverely toxic dose in mice was selected as the starting dose in humans (18 mg/m2). Primary objectives of this study were to establish a safe dose of intravenously administered MLN2704, determine the pharmacokinetics of measurable components of MLN2704 after a single administration, define the immunogenicity of MLN2704, and obtain preliminary evidence of antitumor activity in patients with progressive metastatic castration-resistant prostate cancer.
Patient Selection Patients with histologically proven prostate cancer and progressive castration-resistant metastatic disease were eligible for enrollment. Progressive castration-resistant metastatic disease required a castrate level of testosterone  50 ng/dL, documented metastases, and at least one of the following:  three consecutive increases in prostate-specific antigen (PSA); new metastatic lesion(s) on radionuclide bone scan; or progressive tumor lesions on examination and/or cross-sectional imaging.
Patients previously receiving an antiandrogen must have shown disease progression after antiandrogen withdrawal. Luteinizing hormone-releasing hormone agonist therapy was continued for the treatment duration or discontinued with a sufficient wash-out period. Any corticosteroids must have been discontinued
Baseline and Follow-Up Evaluations
MLN2704
Drug Administration and Dose Escalation
DLT was defined as any of the following toxicities: grade 4 thrombocytopenia, requirement for platelet transfusion, febrile neutropenia,
Pharmacokinetics
Immunogenicity Sampling and Assays
Repeat Dosing
Criteria for Evaluation and End Point Definitions
Patient Characteristics Baseline demographics and disease characteristics of 23 patients accrued between November 18, 2002 and October 27, 2003 are listed in Table 1. Eighteen patients (78%) had been treated with more than three prior hormonal manipulations, and 12 patients (52%) received prior chemotherapy, including taxanes in eight patients (35%).
Dose Escalation The dose-escalation scheme is presented in Table 2. In the first five dose levels (18 to 92 mg/m2), no patient experienced a grade 2 non-DLT or DLT, allowing enrollment of one patient per cohort. From the sixth dose level (120 mg/m2), cohorts of three patients per dose level were enrolled. One patient enrolled at the tenth dose level (343 mg/m2) developed a DLT, and subsequently, three additional patients were enrolled at 343 mg/m2 without DLT.
Toxicities No grade 4 toxicities or deaths occurred on study, and no patients discontinued because of drug-related adverse events. Drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including one of three patients treated at 264 mg/m2 (lymphopenia) and two of six patients treated at 343 mg/m2 (DLT febrile neutropenia, leukopenia, lymphopenia, and transient elevation in ALT after the third dose).
Toxicities occurring in
Hepatic toxicity. Hepatic transaminases were asymptomatically elevated in one of three patients at 120 mg/m2 and five of six patients at 343 mg/m2. Levels typically peaked 7 days after MLN2704 administration and declined to grade 1 by day 28. Transaminase elevations reached grade 3 in only one patient after the third dose at 343 mg/m2. This patient did not have liver metastases. All patients’ hepatic transaminase levels returned to normal after discontinuation of treatment.
GI toxicity.
Mild (grade
Neurotoxicity.
Grade
Miscellaneous toxicities.
Infusion-related rigors (four patients) were managed with routine intervention. Fatigue developed in the majority of patients (15 of 23 patients, 65%); most cases were grade
Pharmacokinetics
Immunogenicity Samples from all 23 patients were evaluated. No antibodies were detected to MLN2704, MLN591, or DM1 at any time point
Antitumor Effects
The patient who developed a DLT after one dose (343 mg/m2) had experienced disease progression on treatment with docetaxel and mitoxantrone plus prednisone before enrollment. MLN2704 was resumed at 264 mg/m2 12 weeks after the first dose. His PSA subsequently declined from 44.8 ng/mL at baseline to 21.0 ng/mL after 100 days. He received a total of four doses without incident. Treatment was discontinued 6 months after the first dose because of increased PSA. Six additional patients treated at doses 156 mg/m2 had stable PSA levels for 26 to 86 days. Measurable disease. Of the two assessable patients treated at 264 mg/m2, one achieved a partial response (for 21.6 weeks), and the other had stable disease. Overall, four of 10 assessable patients had stable disease at the 3-month assessment, including both assessable patients treated at 343 mg/m2.
Exposure
In the first clinical trial involving the PSMA antibody-targeted chemotherapeutic MLN2704, we demonstrate that it can be administered intravenously every 4 weeks in patients with progressive castration-resistant disease, with mild toxicities, predictable pharmacokinetics, and no measurable immunogenicity. Only one patient experienced DLT after a single dose of MLN2704, which involved an episode of uncomplicated febrile neutropenia in a heavily pretreated patient at the highest dose level. Interestingly, this was the only significant hematologic toxicity observed. On expansion of the 343 mg/m2 dose level, no additional DLT occurred. Repeated doses of MLN2704 were well tolerated. From 72 total administered doses, only three patients had drug-related grade 3 toxicities (febrile neutropenia, transient grade 3 elevation in ALT, and lymphopenia). One patient discontinued treatment after 14 cycles as a result of disease progression and grade 2 neuropathy. Low-grade toxicities frequently observed on this trial were primarily constitutional, GI, and neurologic. Drug-related neuropathy was observed only in patients treated at the two highest doses—in two of three patients treated at 264 mg/m2 and four of six patients treated at 343 mg/m2. The etiology of these toxicities is not clear. PSMA expression is low in normal tissues such as the intestine, brain, and proximal renal tubule cells,2,21 and there has been no documentation of PSMA expression in the liver that could explain the cyclical increases in transaminases that occurred approximately 7 days after Cmax was reached. This adverse effect profile is more likely to be related to deconjugation of maytansinoid from MLN591 in the peripheral circulation. Indeed, in phase I studies with maytansine, DLTs included neurotoxicity and GI events. Furthermore, a phase I trial of cantuzumab mertansine, a DM1 immunoconjugate directed against CanAg, reported similar pharmacokinetic and adverse effect profiles.11 Immunoconjugates with less labile linkers may offer a way to decrease the concentration of deconjugated DM1 and any toxicity it causes. For example, an antibody-DM1 conjugate with a thioether linker has been shown to be less labile and to have similar potency in vitro as a disulfide-linked antibody-DM4 conjugate22; however, conjugates with thioether linkers have shown lower activity in vivo than those with disulfide linkages.22,23 Another approach that has been successfully demonstrated is to use a stable peptide linker that is preferentially cleaved by intracellular proteases.24 Hepatic toxicity has also been postulated to be a class effect of therapeutic immunoconjugates in general because clearance of antibody conjugates is ultimately mediated by the reticuloendothelial system.
The antitumor effects observed in this study provide proof-of-principle of the antibody-drug targeting approach. Further validation of the targeting of PSMA is provided by radioimmunopharmaceutical studies; PSA and measurable disease reductions occurred in a phase I trial of yttrium-90–labeled MLN591,6 and a Although dose escalation could have proceeded beyond the highest planned dose to define the maximum-tolerated dose, it was not pursued because of the clinical activity and tolerability of MLN2704 at the dose levels explored and the dose-dependent peripheral neuropathy. Instead, because of emerging preclinical data suggesting improved efficacy with more frequent dosing, the 4-week dosing schedule was abandoned in favor of a second phase I/II trial exploring alternative dosing schedules.25 Additional phase I studies are ongoing to determine optimal dose and frequency of administration of this novel immunoconjugate and to explore its potential for antitumor activity in metastatic prostate cancer.25
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Iain J. Webb, Millennium Pharmaceuticals Inc (C) Consultant or Advisory Role: Mario Eisenberger, Sanofi-Aventis (C), Centocor (U), Cytogen (C) Stock Ownership: Iain J. Webb, Millennium Pharmaceuticals, Inc Honoraria: Mario Eisenberger, Sanofi-Aventis Research Funding: Mario Eisenberger, Sanofi-Aventis, Centocor, Celegene; Howard I. Scher, Millennium Pharmaceuticals Inc, Cytogen Expert Testimony: None Other Remuneration: None
Conception and design: Matthew D. Galsky, W. Kevin Kelly, Iain J. Webb, Howard I. Scher Financial support: Iain J. Webb Provision of study materials or patients: Matthew D. Galsky, Mario Eisenberger, W. Kevin Kelly, Susan F. Slovin, Howard I. Scher Collection and assembly of data: Matthew D. Galsky, Sandra Moore-Cooper, Anthony DeLaCruz, Iain J. Webb, Howard I. Scher Data analysis and interpretation: Matthew D. Galsky, Yih Lee, Iain J. Webb, Howard I. Scher Manuscript writing: Matthew D. Galsky, Mario Eisenberger, Susan F. Slovin, Iain J. Webb, Howard I. Scher Final approval of manuscript: Matthew D. Galsky, Mario Eisenberger, Susan F. Slovin, Howard I. Scher
Pharmacokinetic Assays Three pharmacokinetic assays were used to measure total J591, J591-DM1, and free J591. Quantitative determination of total J591 in human serum. Enzyme-linked immunosorbent assay (ELISA) plates were coated with anti-J591 idiotypic antibody to capture total J591 (MLN2704 and J591) from the test samples. Standard curves using MLN2704 concentrations ranging from 1.25 to 80 ng/mL diluted in 1% pool human serum from healthy donors were run on each plate. The amount of total J591 antibodies that was captured in each well was detected using F(ab')2 fragment mouse antihuman immunoglobulin G (IgG), Fc specific conjugated to horseradish peroxidase (HRP). Bound conjugate was visualized by addition of a substrate solution (tetramethylbenzidine [TMB]), and the intensity of the color was measured at 650 nm. For each sample dilution, the mean of the duplicates was calculated, and the concentration of total J591 was extrapolated from the standard curve using a four-parameter curve-fitting equation. The lower limit of quantitation (LLOQ) for this assay was 750 ng/mL in serum. Quantitative determination of J591-DM1 in human serum. ELISA plates were coated with anti-J591 idiotypic antibody to capture total J591 (MLN2704 and J591) from the test samples. Standard curves using MLN2704 concentrations ranging from 1.25 to 80 ng/mL diluted in 1% pool human serum from healthy donors were run on each plate. The amount of total J591 antibodies that was captured in each well was detected using mouse antimertansine (drug maytansinoid-1 [DM1]) conjugated to HRP. Bound conjugate was visualized by addition of a substrate solution (TMB), and the intensity of the color was measured at 650 nm. For each sample dilution, the mean of the duplicates was calculated, and the concentration of total J591 was extrapolated from the standard curve using a four-parameter curve-fitting equation. The LLOQ for this assay was 750 ng/mL in serum. Quantitative determination of free J591 in human serum. An accurate, sensitive, and reproducible method was validated for the quantitation of free J591 antibody, also known as deconjugated J591, in human serum using an indirect ELISA. Anti-DM1, a monoclonal antibody provided by Millennium Pharmaceuticals, Inc (Cambridge, MA), was used to remove J591-DM1 from the free J591, and then the levels of free J591 in the supernatant were measured using anti-J591 (Millennium Pharmaceuticals, Inc), an anti-idiotype antibody specific for J591 and J591-DM1. The method required a sample pretreatment step in which J591-DM1 was separated from free J591 by incubating the sample in a microtiter plate coated with anti-DM1. Because the anti-DM1 coated wells have a limited binding capacity, the separation step was performed twice to ensure complete removal of J591-DM1. Levels of free J591 were measured using the assay for total J591, in which anti-J591 idiotypic antibody was coated onto another microtiter plate and standard, controls, and supernatants from the two depletion steps, containing free J591, were added to the wells. Any total J591 present bound to the immobilized anti-J591 and was detected using F(ab')2 fragment mouse antihuman IgG, Fc specific conjugated to HRP. Bound conjugate was visualized by addition of a substrate solution (TMB), and the intensity of the color was measured at 650 nm. For each sample dilution, the mean of the duplicates was calculated, and the concentration of total J591 was extrapolated from the standard curve using a four-parameter curve-fitting equation. The LLOQ for this assay was 750 ng/mL in serum.
Immunogenicity Assays The principle of the first two assays relies on the formation of an antibody bridge between bound solid-phase antigen and solution-phase antigen. In other words, anti-MLN591 (or MLN2704) antibodies present in serum samples that bind by one arm to MLN591 (or MLN2704) immobilized to the plate can also bind biotin-labeled MLN591 (or MLN2704) added subsequently in solution, thereby bridging the two antigens. Bound biotin-labeled MLN591 (or MLN2704) was then detected using streptavidin conjugated to HRP. This was followed by addition of a chromogenic substrate solution (TMB), and the intensity of the color was measured at 650 nm. A pool of 10 individual sera from healthy donors served as a negative control (diluted 1:100) to evaluate a cut point above which serum samples were considered positive for human antihuman antibodies. An anti-MLN591 idiotypic antibody was used in the assay as positive control. The minimum required dilution was 100. Samples were first screened in duplicate on coated plates at dilutions of 100 and 1,000. Samples that were negative at both dilutions were reported as titer less than 100. Samples that tested positive at either dilution were further titrated on coated plates and on specificity (noncoated) plates. Specificity plates were treated similarly to the coated plates except that they were not coated with the analyte of interest (MLN591 or MLN2704). The reported titer corresponded to the inverse of the highest dilution of a sample that tested positive (above or equal to the cut point value), and the specificity of this sample was greater than 1.5. The following formula was used to calculate the sample specificity: (Mean optical density [OD] sample on coated plate/mean OD negatives on coated plate)/(mean OD sample on uncoated plate/mean OD negatives on uncoated plate) The cut point was calculated as follows: mean OD of the individual negative controls (at dilution 100) + 1.96 the standard deviation of the individual negative controls. Detection of anti-MLN591 antibodies. In this assay, plates were coated with MLN591, human serum spiked with an anti-MLN591 idiotypic antibody was added as positive control, and bound antibodies to MLN591 were detected by the addition of biotin-conjugated MLN591 followed by HRP-conjugated streptavidin. Qualitative measurement was made by the addition of a colorimetric substrate. Detection of anti-MLN2704 antibodies. In this assay, plates were coated with MLN2704, human serum spiked with an anti-MLN591 idiotypic antibody was added as positive control, and bound antibodies to MLN2704 were detected by the addition of biotin-conjugated MLN2704 followed by HRP-conjugated streptavidin. Qualitative measurement was performed by addition of a colorimetric substrate. Detection of anti-DM1 antibodies. In this assay, plates were coated with DM1 coupled to bovine serum albumin. Human serum spiked with an anti-DM1 monoclonal antibody was added as positive control, and any bound antibodies to DM1 were detected by the addition of a HRP-conjugated goat antimouse IgG. Qualitative measurement was performed by addition of a colorimetric substrate.
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.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
