title: A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound, administered as a 24-h continuous infusion in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent.
  
  
  METHODS
  In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3-6 patients: 600, 1,200, 2,000, and 2,500 mg.
  
  
  RESULTS
  Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses >2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses.
  
  
  CONCLUSIONS
  When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, AZ 85258, USA. mgordon@azpoh.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Robert
authors.initials: R
authors.lastname: Ilaria
authors.forename: Dinesh P
authors.initials: DP
authors.lastname: de Alwis
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.forename: Scott
authors.initials: S
authors.lastname: McKane
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Wagner
authors.forename: Katherine Y
authors.initials: KY
authors.lastname: Look
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C534068:N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide; D013449:Sulfonamides