title: A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia.
abstract: Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m(2)/h, 32 mg/m(2)/h or 24 mg/m(2)/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations.
authors.affiliation: Haematology Service Division of Cancer Medicine, Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, University of Melbourne, Parkville, Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Seymour
authors.affiliation: St. Mary's Hospital, Seoul, South Korea.
authors.forename: D W
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Merck & Co., Inc, Whitehouse Station, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Rubin
authors.affiliation: Merck & Co., Inc, Whitehouse Station, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Haregewoin
authors.affiliation: Merck & Co., Inc, Whitehouse Station, NJ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Clark
authors.affiliation: Merck & Co., Inc, Whitehouse Station, NJ, USA.
authors.forename: P
authors.initials: P
authors.lastname: Watson
authors.affiliation: Haematology, SA Pathology, Adelaide, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Herlev University Hospital, Herlev, Denmark.
authors.forename: I
authors.initials: I
authors.lastname: Dufva
authors.affiliation: Hospital Universitario Ramon y Cajal, Madrid, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Jimenez
authors.affiliation: Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.
authors.forename: F-X
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: Hopital de Versailles, Université Versailles Saint Quentin en, Yvelines, France.
authors.forename: P
authors.initials: P
authors.lastname: Rousselot
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.affiliation: University of Bologna, Bologna, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: University of Bologna, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Papayannidis
authors.affiliation: Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Nagler
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: Giles
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000008:administration & dosage*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D016044:Fusion Proteins, bcr-abl; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines