title: Phase I study of MLN8237--investigational Aurora A kinase inhibitor--in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies.
  
  
  METHODS
  Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days' rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21-day cycles.
  
  
  RESULTS
  Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease.
  
  
  CONCLUSIONS
  The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma.
authors.affiliation: CTRC at the University of Texas Health Science Center at San Antonio, The Institute for Drug Development, San Antonio, TX, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Shea
authors.forename: André
authors.initials: A
authors.lastname: Goy
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Berdeja
authors.forename: Craig B
authors.initials: CB
authors.lastname: Reeder
authors.forename: Kevin T
authors.initials: KT
authors.lastname: McDonagh
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: Hadi
authors.initials: H
authors.lastname: Danaee
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ecsedy
authors.forename: Huifeng
authors.initials: H
authors.lastname: Niu
authors.forename: Ely
authors.initials: E
authors.lastname: Benaim
authors.forename: Swaminathan Padmanabhan
authors.initials: SP
authors.lastname: Iyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A