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Dr. Kaufman - ASH 2008 - First Trial of Humanized Anti-CD74 Monoclonal Antibody (MAb), Milatuzumab, in Multiple Myeloma
Jonathan Kaufman, MD
Emory University School of Medicine
Winship Cancer Institute
Atlanta Georgia
USA
12.28.08


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Jonathan Kaufman, MD, Ruben Niesvizky, MD, Edward A. Stadtmauer, MD, Asher Chanan-Khan, MD, David Siegel, MD, PhD, Heather Horne, Nick Teoh, PhD, Matthew J. Leoni, MD, William A Wegener, MD, PhD and David M. Goldenberg, ScD, MD

BACKGROUND: CD74 (HLA-DR-associated invariant chain) is highly expressed in multiple myeloma and other B-cell lymphomas, rapidly internalized, and a promising target for therapeutic intervention in these diseases, including conjugated drug delivery.  Milatuzumab (hLL1) is a humanized MAb which recognizes CD74 and has shown efficacy in various preclinical B-lymphoma models, particularly multiple myeloma, but with rapid blood clearance seen in cynomolgus monkeys.  The goal of this first clinical study of milatuzumab is to evaluate the safety, tolerability, and feasibility of twice-weekly dosing in multiple myeloma; to determine a maximum tolerated dose (MTD); to obtain preliminary information on efficacy, pharmacodynamics, and immunogenicity; and to identify acceptable doses for subsequent studies.

METHODS: A multicenter study was initiated in patients with relapsed/refractory multiple myeloma who had failed at least 2 standard therapies. All patients received milatuzumab intravenously twice weekly for 4 weeks, and then were evaluated for safety and efficacy over 12 weeks, with responding patients continuing long-term follow-up. To determine the MTD, patients were entered in cohorts treated at escalating doses according to a 3+3 design. Adverse events and safety laboratories were evaluated by NCI CTC v3 toxicity grades, with any Grade 3-4 toxicity considered dose-limiting toxicity (DLT). Efficacy assessments used serum and urine M-protein electrophoresis and other evaluations as required for classifying responses by EBMT criteria, while pharmacokinetics and immunogenicity were evaluated by serum milatuzumab levels and human anti-milatuzumab antibody (HAHA) titers, respectively, using an ELISA assay.

RESULTS: Eighteen patients (9F/9M, median age 61) have now received milatuzumab at 1.5 mg/kg (n=8), 4.0 mg/kg (n=9) or 8.0 mg/kg (n=1).  They had multiple myeloma for 0.9-16.8 years (median 5.6), predominantly IgG subtype, were heavily pretreated (4.5 median prior treatments), and were either Durie-Salmon stage II (n=10) or III (n=8).  One DLT (Grade 3 infusion reaction) was observed at 1.5 mg/kg.  Subsequently, increased premedication as well as slow drug infusions resulted in improved tolerability (transient mild-moderate (Grade 1-2) infusion reaction), including the single patient treated at 8.0 mg/kg.  At 4.0 mg/kg, one patient had a DLT with an acute hemoglobin drop to Grade 3 levels without definitive explanation.  Additionally, one other patient at the 1.5-mg/kg dose had a serious event of bacterial meningitis post-treatment, which resolved.  No pattern of other adverse reactions has been seen, nor effects on routine laboratories, including serum chemistries, CBC, serum immunoglobulins, B- or T-lymphocytes. Milatuzumab is rapidly cleared from serum, with little accumulation at successive infusions for patients treated at 1.5 or 4.0 mg/kg (mean peak serum levels, respectively: 13.5 and 38.0 µg/mL at 1st infusion, 13.0 and 53.6 µg/mL at last infusion), and results pending at 8.0 mg/kg.  In all post-treatment samples evaluated, HAHA results have been negative.  At 1.5 mg/kg, there were no objective responses, and efficacy results are not yet available at 8.0 mg/kg, but at 4.0 mg/kg, 3 patients have had stable disease by EBMT criteria at 8+ to 12+ weeks after treatment.

CONCLUSIONS: These initial results indicate that milatuzumab may be safely administered to patients with multiple myeloma. The occurrence of stable disease in several patients in encouraging, in spite of rapid clearance at twice-weekly doses of 1.5 mg/kg and 4.0 mg/kg.  Accrual of the next cohort receiving doses of 8.0 mg/kg is ongoing.

 


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