title: A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors.
abstract: OBJECTIVE
  This phase I study was carried out to determine the phase II recommended dose of tasisulam sodium (hereafter, tasisulam), a novel anticancer agent with a unique mechanism of action.
  
  
  METHODS
  Tasisulam was administered intravenously, every 21 days, in patients with refractory solid tumors using a three-plus-three dose-escalation schema.
  
  
  RESULTS
  Fifty-three patients were enrolled; the first 34 were treated with a flat dose of tasisulam of up to 2,400 mg, the dose level at which all three patients had dose-limiting toxicity (DLT). Controlling for C(max) proved important to reduce the risk of toxicity; therefore, we initially focused on identifying which parameters explained C(max) (end-of-infusion concentration) variability. Pharmacokinetic analysis indicated that C(max) negatively correlates with lean body weight (LBW). Thus, the dosing regimen was revised using a LBW-based algorithm targeting a specific C(max). A loading/chronic dose paradigm was then implemented as pharmacokinetic results revealed a long terminal half-life of tasisulam, likely because of its high-affinity albumin binding. C(max)-based dose escalation was stopped at the 420-μg/mL cohort, in which one of the 16 patients had DLT (transient hepatic transaminase elevation); grade 3/4 hematologic toxicity was noted in later cycles in three patients. Although response was not a primary objective, 33% of heavily pretreated patients with post-dose radiological assessments had stable disease.
  
  
  CONCLUSIONS
  Implementation of a novel targeted C(max)-based dosing regimen allowed for the recommendation of a phase II tasisulam dose (loading dose of 420 μg/mL targeted C(max) with all subsequent doses administered at 65% of chronic dose given every 21 days) despite pharmacological challenges posed by high albumin binding.
authors: H. Lee Moffitt Cancer Center, Tampa, FL, USA. simong@musc.edu
authors: George R
authors: GR
authors: Simon
authors: Robert L
authors: RL
authors: Ilaria
authors: Mika A
authors: MA
authors: Sovak
authors: Charles C
authors: CC
authors: Williams
authors: Eric B
authors: EB
authors: Haura
authors: Ann L
authors: AL
authors: Cleverly
authors: Amanda K
authors: AK
authors: Sykes
authors: Margaret M
authors: MM
authors: Wagner
authors: Dinesh P
authors: DP
authors: de Alwis
authors: Christopher A
authors: CA
authors: Slapak
authors: Mary A
authors: MA
authors: Miller
authors: David R
authors: DR
authors: Spriggs
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C534068:N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide; D013449:Sulfonamides