Correlation Between Serum Ofatumumab Concentrations, Baseline Patient Characteristics and Clinical Outcomes in Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ofatumumab.

Abstract 3433 Poster Board III-321 Introduction Monoclonal antibody (mAb) therapies represent an important clinical advance for patients (pts) with CLL, yet little is known about the pharmacokinetics (PK) and pharmacodynamics of mAb therapy in these pts. Ofatumumab is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity in vitro . Ofatumumab is being evaluated in a pivotal trial for pts with fludarabine-refractory CLL also refractory to alemtuzumab (FA-ref; n=59) or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy (BF-ref; n=79). Overall response rate (ORR; primary endpoint) was 58% in FA-ref and 47% in BF-ref pts at an interim analysis; median progression-free survival (PFS) was 5.7 and 5.9 months, respectively. We evaluated relationships between baseline factors and ofatumumab PK and between PK parameters and treatment outcomes from the pivotal trial. Patients and Methods Pts received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2-12, 2000 mg). Response (1996 NCI-WG criteria) was assessed by an Independent Review Committee over 24 weeks of therapy. Blood samples for PK analysis were collected at Dose 1, Dose 8 (last weekly dose), and Dose 12 (last monthly dose). A population PK model was employed that included data from a previous study (Coiffier et al , Blood 2008;111:1094). For Dose 1, C max was determined; for Doses 8 and 12, C max , C min , AUC, clearance (CL), volume of distribution (Vss) and t ½ were determined. The relationships between baseline pt characteristics and disease factors and PK parameters were evaluated by multivariate regression analysis. Associations between PK and ORR or PFS were explored using univariate and multivariate logistic regression or Cox regression analyses. Results 90% of the 154 pts received 8 weekly infusions of ofatumumab and 55% received all 12 infusions. PK parameters were similar between FA-ref and BF-ref pts. In multivariate analysis, higher C max at Dose 1 was significantly associated with lower % of bone marrow infiltration (p max and C min at Dose 8 were associated with increased likelihood of response (Table); in addition, significantly higher C max , C min and AUC were observed in responders versus non-responders (p max , AUC and C min and lower CL at both Doses 8 and 12 were significantly correlated with longer PFS (p Conclusions These data demonstrate that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. The pivotal study is ongoing, and further analyses of associations between disease-related factors, PK and treatment response will be performed at study completion. Such analyses will help us to better understand the response kinetics of biological therapy and to optimize the dose. Disclosures Osterborg: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Biilmann Ronn: Genmab: Employment. Jewell: GlaxoSmithKline: Employment, Equity Ownership. Kipps: Physicians9 Educational Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Mayer: GlaxoSmithKline: Consultancy. Stilgenbauer: GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Hellmann: Novartis, BMS: Consultancy, Honoraria. Robak: GlaxoSmithKline, Roche: Advisory Board, Research Funding. Furman: GlaxoSmithKline: Consultancy, Speakers Bureau. Hillmen: GlaxoSmithKline: Consultancy, Honoraria for Advisory Boards. Trneny: GlaxoSmithKline: Honoraria. Padmanabhan: GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Kozak: GlaxoSmithKline, Amgen: Consultancy. Chan: GlaxoSmithKline: Employment. Arning: GlaxoSmithKline: Employment, Equity Ownership. Losic: Genmab: Employment, Stock Ownership. Davis: GlaxoSmithKline: Employment, Stock ownership. Wilms: Genmab: Employment, Equity Ownership. Russell: Genmab: Employment, Equity Ownership. Wierda: Genmab, GlaxoSmithKline: Honoraria, Research Funding.