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Dr. Zonder - Phase I Trial of HuLuc63 in Multiple Myeloma
Jeffrey A. Zonder, MD
Karmanos Cancer Institute
Detroit, Michigan

"So far it's clear that HuLuc63 is well tolerated in relapsed and refractory patients, and we are hopeful that the stabilization we saw in some patients is a signal that we are going to see activity as we escalate the dose further according to the design of the program."
Dr. Jeffrey Zonder

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[1180] Phase I Trial of HuLuc63 in Multiple Myeloma. Session Type: Poster Session, Board #334-IWilliam Bensinger, Jeffrey Zonder, Seema Singhal, Ann Mohrbacher, Robert M. Dean, Frits van Rhee, Ahmad-Samer Al-Homsi, Nikhil C. Munshi, Edward R. Conner, Mohamad A. Hussein Fred Hutchinson Cancer Center, Seattle, WA, USA; Karmanos Cancer Center, Detroit, MI, USA; Northwestern University, Chicago, IL, USA; Hematology, Keck School of Medicine, Los Angeles, CA, USA; Hematologic Oncology and Blood Disorders, The Cleveland Clinic, Taussig Cancer Center, Cleveland, OH, USA; Myeloma Institute for Research and Therapy, University of Arkansas Medical Sciences, Little Rock, AR, USA; University of Massachusetts Medical Center, Worcester, MA, USA; Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; PDL Biopharma, Fremont, CA, USA; H. Lee Moffitt Cancer Center, Tampa, FL, USABackground: HuLuc63 is a humanized monoclonal antibody directed against CS1 that has demonstrated potent in vivo and in vitro activity against myeloma cells in pre-clinical models. CS1 is a cell surface glycoprotein expressed at high levels on myeloma cells, plasma cells and to a lesser extent on a subset of CD8 + lymphocytes and natural killer (NK) cells. A Phase I study was initiated to evaluate the maximum tolerated dose (MTD) of HuLuc63 in a population of relapsed refractory multiple myeloma patients who have been exposed to at least two prior therapies. In a traditional phase 1 design, six potential dosing cohorts are planned with 3 to 6 patients enrolled per cohort to evaluate safety, pharmacokinetics (PK), biologic activity and clinical response. Each course of HuLuc63 is given IV at the same dose every 2 weeks for a total of 4 doses at a level of 0.5, 1, 2.5, 5, 10, 20 mg/kg. An additional 4 doses may be administered if the patient has demonstrated at least stable disease during the initial course of therapy. To date, a total of 7 patients have been treated at 2 dose levels; 3 in the 0.5 mg/kg cohort and 4 in the 1.0 mg/kg cohort. Median patient age is 64 years and the median number of prior therapies is five. An additional patient was enrolled in the 1.0 mg/kg cohort as a patient in that cohort had a 2-week delay in receiving his second dose due to worsening pain at the site of a pre-existing lytic bone lesion. No dose-limiting toxicities have occurred. Infusions were well tolerated, with grade 1 and 2 toxicities occurring during or after the first dose including chills (2 patients), flushing, pyrexia, rigors, dyspnea and fatigue. Patients who reported first dose reactions were pretreated with acetaminophen and diphenhydramine prior to subsequent doses and only one patient reported fatigue after the second dose. Four serious adverse events have occurred in 2 patients which were considered unrelated to HuLuc63. These include migraine headache (twice in the same patient), congestive heart failure and hypercalcemia. Two patients discontinued therapy prematurely due to progressive disease but all other patients have received 4 doses of HuLuc63. No clinical responses have been observed. In xenograft mouse models, a consistent drug level of 10 mcg / mL was required to show minimal biologic activity. Preliminary PK data reveals that peak serum drug levels for the 0.5 mg/kg dosing cohort reached 10 mcg / mL, which was sufficient to achieve CS 1 saturation of at least 70% on the antigen rich NK cell subset. Drug levels dropped below 1 mcg/mL by day 7, however, coinciding with a decrease in saturation. This indicates that the higher doses to be used in subsequent cohorts may achieve and surpass sustained concentrations in patients above this level. Thus far, HuLuc63 appears to be well tolerated in patients with multiple myeloma. Enrollment is continuing to determine the MTD.Abstract #1180 appears in Blood, Volume 110, issue 11, November 16, 2007Keywords: Myeloma|Monoclonal Antibody|TherapyDisclosure: Employment: Edward R. Conner, MD is an employee of PDL Biopharma.Saturday, December 8, 2007 5:30 PMSession Info: Poster Session: Myeloma: Experimental Therapies for Multiple Myeloma (5:30 p.m.-7:30 p.m.)

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