title: Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective aurora a kinase inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.
  
  
  METHODS
  Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.
  
  
  RESULTS
  Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.
  
  
  CONCLUSIONS
  The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.
authors: Hematology and Medical Oncology Department, Hospital Clinico, INCLIVA, University of Valencia, Valencia, Spain.
authors: Andres
authors: A
authors: Cervantes
authors: Elena
authors: E
authors: Elez
authors: Desamparados
authors: D
authors: Roda
authors: Jeffrey
authors: J
authors: Ecsedy
authors: Teresa
authors: T
authors: Macarulla
authors: Karthik
authors: K
authors: Venkatakrishnan
authors: Susana
authors: S
authors: Roselló
authors: Jordi
authors: J
authors: Andreu
authors: Jungah
authors: J
authors: Jung
authors: Juan Manuel
authors: JM
authors: Sanchis-Garcia
authors: Adelaida
authors: A
authors: Piera
authors: Inma
authors: I
authors: Blasco
authors: Laura
authors: L
authors: Maños
authors: José-Alejandro
authors: JA
authors: Pérez-Fidalgo
authors: Howard
authors: H
authors: Fingert
authors: Jose
authors: J
authors: Baselga
authors: Josep
authors: J
authors: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D064127:Aurora Kinases; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001706:Biopsy; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013280:Stomatitis / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases