title: First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors.
abstract: BACKGROUND
  ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026.
  
  
  METHODS
  Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25-800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1.
  
  
  RESULTS
  The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration-time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38%), fatigue (35%), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50%; 95% confidence interval 25-75%) and seven patients (44%) achieved stable disease.
  
  
  CONCLUSIONS
  ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors.
  
  
  BACKGROUND
  ClinTrials.gov: NCT01284192.
authors.affiliation: Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, 4501 X St #3016, Sacramento, CA, 95817, USA. thli@ucdavis.edu.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Li
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.|Present address: Yale Smilow Cancer Center, New Haven, CT, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Section of Hematology/Oncology, Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago Medicine, Chicago, IL, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Erkut
authors.initials: E
authors.lastname: Bahceci
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Ball
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Yuen
authors.affiliation: South Texas Accelerated Research Therapies (START) Center for Cancer Care, San Antonio, TX, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D000077547:Crizotinib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: C000595153:ASP3026; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013450:Sulfones; D014227:Triazines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK inhibitor; ASP3026; Neoplasms; Pharmacokinetics; Phase I