title: An open-label, single-arm, phase 1 study to assess biomarker effects, efficacy and safety of ofatumumab in patients with refractory chronic lymphocytic leukemia.
abstract: This open-label, phase 1 study evaluated the effects of ofatumumab on QTc intervals, safety, efficacy, B-cell and neutrophil counts, complement levels, and cytokine and chemokine concentrations. Fourteen patients with fludarabine-refractory chronic lymphocytic leukemia received 12 ofatumumab infusions. A higher maximum infusion rate of 400 mL/h was tested at the first two doses and was well tolerated. The 43% overall response rate was similar to previous data (42-51%). B-cell depletion was observed along with complement consumption; median C2 and CH50 levels appeared lower during monthly dosing in patients who responded. Responding patients appeared to have higher median levels of certain pro-inflammatory cytokines and lower median levels of certain immunotolerant cytokines than patients who did not respond. Ofatumumab-induced complement-dependent cytotoxicity activity can be detected clinically by measuring complement and may be associated with clinical activity. The potential relationship between changes in complement or cytokines and clinical response to ofatumumab warrants further study.
authors.affiliation: a Auckland Clinical Studies Ltd , Grafton, Auckland , New Zealand.
authors.forename: William Nigel
authors.initials: WN
authors.lastname: Patton
authors.affiliation: b GlaxoSmithKline Medicines Research Unit, Prince of Wales Hospital , Randwick, New South Wales , Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Lindeman
authors.affiliation: c Christchurch Clinical Services Trust Ltd , Christchurch , New Zealand.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Butler
authors.affiliation: d UCSD Moores Cancer Center , La Jolla , CA , USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: e GlaxoSmithKline, Research Triangle Park , NC , USA.
authors.forename: Roxanne C
authors.initials: RC
authors.lastname: Jewell
authors.affiliation: e GlaxoSmithKline, Research Triangle Park , NC , USA.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Laubscher
authors.affiliation: f Pharstat, Inc. , Raleigh , NC , USA.
authors.forename: Yan Yan
authors.initials: YY
authors.lastname: Zhou
authors.affiliation: e GlaxoSmithKline, Research Triangle Park , NC , USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lewis
authors.affiliation: g GlaxoSmithKline , Collegeville , PA , USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Sedoti
authors.affiliation: g GlaxoSmithKline , Collegeville , PA , USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Witman
authors.affiliation: f Pharstat, Inc. , Raleigh , NC , USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: g GlaxoSmithKline , Collegeville , PA , USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology; D001402:B-Lymphocytes; D015415:Biomarkers; D066126:Cardiotoxicity / Q000188:drug therapy; D003165:Complement System Proteins / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007239:Infections / Q000209:etiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D019233:Retreatment; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; D003165:Complement System Proteins; D014740:Vidarabine; C527517:ofatumumab; C024352:fludarabine
keywords: CD20; Chronic lymphocytic leukemia; biomarkers; chemokines; complement; cytokines; ofatumumab