title: Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose.
abstract: OBJECTIVE
  This phase 1 study assessed the pharmacokinetics (PK), maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, and preliminary efficacy of the investigational Aurora A kinase inhibitor, alisertib, in East Asian patients with advanced solid tumors or lymphomas.
  
  
  METHODS
  Patients received alisertib twice-daily (BID) for 7 days in 21-day cycles. Doses were escalated (3 + 3) from 30 mg BID based on cycle 1 dose-limiting toxicities (DLTs) until the MTD, followed by expansion for PK/safety characterization.
  
  
  RESULTS
  Thirty-six patients (61 % Chinese, 36 % Korean, 3 % Malay) received alisertib (30 mg BID, n = 30; 40 mg BID, n = 6; median, 2.5 cycles). Alisertib exposures increased approximately dose proportionally, and mean half-life was 16 h. Geometric mean apparent oral clearance (2.65 L/h) was 40 % lower than previous estimates in Western patients, resulting in approximately 70 % higher mean dose-normalized, steady-state exposures (735 nM*h/mg) in East Asian patients. Two patients experienced DLTs at 40 mg BID (grade 3 stomatitis; grade 4 neutropenia); the MTD/RP2D was 30 mg BID. Common toxicities (grade ≥3 at RP2D) were neutropenia (50 %), diarrhea (13 %), and stomatitis (10 %). One patient with extranodal T-/NK-cell lymphoma (nasal type) achieved a partial response and 18 (51 %) had stable disease.
  
  
  CONCLUSIONS
  The MTD/RP2D of alisertib in East Asian patients (30 mg BID) was lower than in Western patients (50 mg BID), consistent with higher systemic exposures in the East Asian population. Alisertib was generally well tolerated and showed signs of antitumor activity in East Asian cancer patients.
authors.affiliation: Clinical Pharmacology, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, karthik.venkatakrishnan@takeda.com.
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.forename: Lim Soon
authors.initials: LS
authors.lastname: Thye
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Brigette
authors.initials: B
authors.lastname: Ma
authors.forename: Ming Huang
authors.initials: MH
authors.lastname: Chen
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Virginia
authors.initials: V
authors.lastname: Kelly
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A