title: The addition of granulocyte-colony stimulating factor shifts the dose limiting toxicity and markedly increases the maximum tolerated dose and activity of the kinesin spindle protein inhibitor SB-743921 in patients with relapsed or refractory lymphoma: results of an international, multicenter phase I/II study.
abstract: This was a phase I study of SB-743921 (SB-921) in patients with relapsed/refractory lymphoma. Previous studies established that neutropenia was the only dose limiting toxicity (DLT). The primary objective was to determine the DLT, maximum tolerated dose (MTD) and efficacy of SB-921 with and without granulocyte-colony stimulating factor (G-CSF). Sixty-eight patients were enrolled, 42 without G-CSF, 26 with G-CSF. In the cohort without G-CSF, SB-921 doses ranged from 2 to 7 mg/m(2), with 6 mg/m(2) being the MTD. In the cohort with G-CSF support, doses of 6-10 mg/m(2) were administered, with 9 mg/m(2) being the MTD, representing a 50% increase in dose density. Fifty-six patients were evaluable for efficacy. Four of 55 patients experienced a partial response (three in Hodgkin lymphoma and one in non-Hodgkin lymphoma, all at doses ≥ 6 mg/m(2)); 19 patients experienced stable disease, 33 patients developed progression of disease. G-CSF shifted the DLT from neutropenia to thrombocytopenia, allowing for a 50% increase in dose density. Responses were seen at higher doses with G-CSF support.
authors: a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , New York , NY , USA.
authors: Owen A
authors: OA
authors: O'Connor
authors: b Memorial Sloan-Kettering Cancer Center , New York , NY , USA.
authors: John
authors: J
authors: Gerecitano
authors: c UNC Linenberger Cancer Center , Chapel Hill , NC , USA.
authors: Henrik
authors: H
authors: Van Deventer
authors: d Sarah Cannon Research Institute , Nashville , TN , USA.
authors: John
authors: J
authors: Hainsworth
authors: a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , New York , NY , USA.
authors: Kelly M
authors: KM
authors: Zullo
authors: e Cytokinetics, Inc. , South San Francisco , CA , USA.
authors: Khalil
authors: K
authors: Saikali
authors: e Cytokinetics, Inc. , South San Francisco , CA , USA.
authors: Joseph
authors: J
authors: Seroogy
authors: e Cytokinetics, Inc. , South San Francisco , CA , USA.
authors: Andrew
authors: A
authors: Wolff
authors: e Cytokinetics, Inc. , South San Francisco , CA , USA.
authors: Rafael
authors: R
authors: Escandón
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D002867:Chromones / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D002867:Chromones; C470243:KIF11 protein, human; C557279:SB 743921; D016179:Granulocyte Colony-Stimulating Factor; D016547:Kinesins
keywords: Hodgkin lymphoma; SB-743921; kinesin spindle protein inhibitor; non-Hodgkin lymphoma