title: ASP9853, an inhibitor of inducible nitric oxide synthase dimerization, in combination with docetaxel: preclinical investigation and a Phase I study in advanced solid tumors.
abstract: OBJECTIVE
  ASP9853 is an inhibitor of inducible nitric oxide (NO) synthase (iNOS) dimerization, which results in decreased NO production. Here, we report preclinical pharmacology of ASP9853 and the impact of ASP9853 in combination with a taxane on tumor volume in vivo. In addition, a Phase I open-label study of ASP9853 plus docetaxel was conducted to assess this combination in patients with advanced solid tumors.
  
  
  METHODS
  The preclinical efficacy of ASP9853 in combination with a taxane was studied in tumor-bearing mice. In the clinic, patients with solid tumors that had progressed or failed to respond to previous therapies were treated with once-daily ASP9853 in combination with docetaxel once every 3 weeks to assess safety and tolerability and to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D) of the combination.
  
  
  RESULTS
  ASP9853 in combination with docetaxel showed greater tumor growth inhibition than docetaxel alone against non-small lung cancer xenografts. Twenty patients were treated with ASP9853 and docetaxel. Five patients experienced neutropenic dose-limiting toxicities. Owing to overall toxicity that limited further dose escalation, the ASP9853 concentrations predicted for efficacy, based on the preclinical data, were not achieved. Due to toxicity and lack of clear efficacy, the study was terminated without determination of MTD or RP2D.
  
  
  CONCLUSIONS
  Inhibition of iNOS by ASP9853 in combination with docetaxel was not tolerable and resulted in the possible potentiation of neutropenia. Manipulation of the iNOS pathway, with or without chemotherapy, appears to be more complicated than initially expected.
authors.affiliation: Section of Hematology/Oncology, The University of Chicago Medicine, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA. jluke@medicine.bsd.uchicago.edu.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Luke
authors.affiliation: Yale Smilow Cancer Center, New Haven, CT, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Krivoshik
authors.affiliation: Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Schuster
authors.affiliation: Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, USA.
authors.forename: Allam
authors.initials: A
authors.lastname: Fakhoury
authors.affiliation: Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Dmuchowski
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D019281:Dimerization; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: C000609273:ASP9853; D000178:Acrylamides; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D052247:Nitric Oxide Synthase Type II
keywords: ASP9853; Docetaxel; Nitric oxide synthase dimerization; Phase I clinical trial; Taxane; Tumor
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