title: Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.
abstract: Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurredviacohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA afathi@partners.org.
authors.forename: Amir T
authors.initials: AT
authors.lastname: Fathi
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Wander
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
authors.forename: Traci M
authors.initials: TM
authors.lastname: Blonquist
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Brunner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Amrein
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Supko
authors.affiliation: Worcester Polytechnic Institute, Department of Biology, Worcester, MA, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Hermance
authors.affiliation: Worcester Polytechnic Institute, Department of Biology, Worcester, MA, USA.
authors.forename: Amity L
authors.initials: AL
authors.lastname: Manning
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Sadrzadeh
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Ballen
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Eyal C
authors.initials: EC
authors.lastname: Attar
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Hobbs
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Joseph
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Perry
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Burke
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Silver
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Foster
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Bergeron
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Aura Y
authors.initials: AY
authors.lastname: Ramos
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Tina T
authors.initials: TT
authors.lastname: Som
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Kaitlyn M
authors.initials: KM
authors.lastname: Fishman
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: McGregor
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Connolly
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Yi-Bin
authors.initials: YB
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003561:Cytarabine; D064096:Aurora Kinase A; D015255:Idarubicin