title: Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors.
abstract: BACKGROUND
  This study was designed to determine the safety, tolerability, and pharmacokinetics (PK) of alisertib (MLN8237) in combination with docetaxel and to identify a recommended dose for the combination.
  
  
  METHODS
  Adults with metastatic cancer were treated on 21-day cycles with alisertib (10, 20, 30, or 40 mg) twice daily on days 1 to 7 or days 1 to 5 and with docetaxel (75 or 60 mg/m(2) ) on day 1. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) for future studies. Secondary objectives included an efficacy assessment and PK analyses of docetaxel and alisertib.
  
  
  RESULTS
  Forty-one patients participated. Eight dose levels were explored with various doses of alisertib and docetaxel. The dose-limiting toxicities were neutropenic fever, neutropenia without fever, stomatitis, and urinary tract infection. The RP2D of this combination was 20 mg of alisertib twice daily on days 1 to 7 and intravenous docetaxel at 75 mg/m(2) on day 1 in 21-day cycles. Eight of the 28 patients (29%) who were efficacy-evaluable had objective responses. These included 1 complete response in a patient with bladder cancer, 6 partial responses in patients with castration-resistant prostate cancer, and 1 partial response in a patient with angiosarcoma. Concomitant administration of alisertib did not produce any clinically meaningful change in docetaxel PK.
  
  
  CONCLUSIONS
  Alisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m(2) on day 1 in a 21-day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524-33. © 2016 American Cancer Society.
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
authors.forename: Julie N
authors.initials: JN
authors.lastname: Graff
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Hahn
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Taylor
authors.affiliation: Millennium Pharmaceuticals, Inc, Takeda Pharmaceutical Company, Limited, Cambridge, Massachusetts.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Millennium Pharmaceuticals, Inc, Takeda Pharmaceutical Company, Limited, Cambridge, Massachusetts.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Millennium Pharmaceuticals, Inc, Takeda Pharmaceutical Company, Limited, Cambridge, Massachusetts.
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.affiliation: Millennium Pharmaceuticals, Inc, Takeda Pharmaceutical Company, Limited, Cambridge, Massachusetts.
authors.forename: E Jane
authors.initials: EJ
authors.lastname: Leonard
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; 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; D015415:Biomarkers; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D001381:Azepines; D015415:Biomarkers; C550258:MLN 8237; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D064096:Aurora Kinase A
keywords: alisertib; aurora A kinase; novel antitumor agents; pharmacokinetics/pharmacodynamics; solid tumors