title: Phase I study of E7820, an oral inhibitor of integrin alpha-2 expression with antiangiogenic properties, in patients with advanced malignancies.
abstract: OBJECTIVE
  This phase I study was conducted to characterize the safety profile, pharmacokinetics, pharmacodynamics, dose-limiting toxicity (DLT), and the maximum-tolerated dose of E7820, a novel oral sulfonamide derivative with antiangiogenic properties, when administered to patients with advanced solid malignancies.
  
  
  METHODS
  Patients received single daily doses of E7820 orally for 28 days in cycle 1, followed by a 7-day no-treatment period, after which time-uninterrupted daily dosing ensued. The starting dose of E7820 was 10 mg/d, which was increased to 20, 40, 70, 100, and 200 mg/d in cohorts of new patients.
  
  
  RESULTS
  Thirty-seven patients [21 male; median age 65 (40-82] were enrolled. At 100 mg/d, 1 patient experienced a DLT consisting of grade 3 neutropenia, thrombocytopenia, and elevated liver enzymes. At the 200-mg dose level, 2 patients experienced grade 4 thrombocytopenia and neutropenia. No partial or complete responses were observed; 8 patients had stable disease (≥ 4 months), including 5 patients with protracted stable disease exceeding 6 months. Mean time to maximum plasma concentration values ranged from 1 to 12 hours, whereas mean terminal half-life values ranged from 5.6 to 8.6 hours. Flow cytometric analysis of platelet integrin α-2 expression showed a sustained greater than 50% decrease beyond day 28 in 3 of 4 patients at 200 mg, whereas moderate (<30%) decreases were observed at 70- and 100-mg dose levels.
  
  
  CONCLUSIONS
  The recommended phase II dose of E7820 is 100 mg/d, based on a fasting schedule. E7820 downregulates integrin α-2 expression in surrogate tissues (platelets) and is associated with stable disease in a wide variety of heavily pretreated malignancies.
authors.affiliation: Institute For Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, Texas, USA. mitam@uthscsa.edu
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.forename: Alain
authors.initials: A
authors.lastname: Mita
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Ricart
authors.forename: Ofelia
authors.initials: O
authors.lastname: Romero
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.forename: Laurel
authors.initials: L
authors.lastname: Hook
authors.forename: Chukwuemeka
authors.initials: C
authors.lastname: Okereke
authors.forename: Ilya
authors.initials: I
authors.lastname: Krivelevich
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Rossignol
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D039421:Integrin alpha2 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009503:Neutropenia / Q000188:drug therapy; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D039421:Integrin alpha2; D013449:Sulfonamides; C468872:N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzene-sulfonamide