title: A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.
abstract: BACKGROUND
  MK-5108 is a potent/highly selective Aurora A kinase inhibitor.
  
  
  METHODS
  A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target.
  
  
  RESULTS
  35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day).
  
  
  CONCLUSIONS
  MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.
authors.affiliation: Division of Oncology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA.
authors.forename: Manik
authors.initials: M
authors.lastname: Amin
authors.affiliation: H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Minton
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.|Yale University, New Haven, CT, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: University Hospitals Case Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Smitha S
authors.initials: SS
authors.lastname: Krishnamurthi
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.|Global Development Oncology, Amgen, Thousand Oaks, CA, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Pickett
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Lunceford
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Darcy
authors.initials: D
authors.lastname: Hille
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.|Advaxis, Inc., Princeton, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mauro
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.affiliation: Division of Oncology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Division of Oncology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Trull
authors.affiliation: Division of Oncology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA. alockhar@dom.wustl.edu.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; D003509:Cyclohexanecarboxylic Acids; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; D064096:Aurora Kinase A
keywords: Aurora A kinase inhibitor; Combination therapy; Docetaxel; Pharmacodynamics; Pharmacokinetics; Tumor response