title: A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma.
abstract: BACKGROUND
  Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin-bound agent that demonstrated activity in a phase 2 melanoma study.
  
  
  METHODS
  In this open-label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin-corrected exposure of 1200-6400 h (hour).μg/mL on day 1) or paclitaxel (80 mg/m(2) on days 1, 8, and 15) every 28 days as second-line treatment.
  
  
  RESULTS
  The study was placed on clinical hold after randomization of 336 patients when a safety review indicated an imbalance of possibly drug-related deaths in the tasisulam arm. Efficacy results for tasisulam versus paclitaxel revealed a response rate of 3.0% versus 4.8%, a median progression-free survival of 1.94 months versus 2.14 months (P = .048), and a median overall survival of 6.77 months versus 9.36 months (P = .121). The most common drug-related grade ≥3 laboratory toxicities (graded according to Common Terminology for Adverse Events [version 3.0]) were thrombocytopenia (18.9%) for patients treated with tasisulam and neutropenia/leukopenia (8.7%) among those receiving paclitaxel. There were 13 possibly related deaths reported to occur on the study, with the majority occurring during cycle 2 in the setting of grade 4 myelosuppression, all in the tasisulam arm. Investigation of the unexpectedly high rate of hematologic toxicity revealed a subset of patients with low tasisulam clearance, leading to drug accumulation and high albumin-corrected exposure in cycle 2.
  
  
  CONCLUSIONS
  Although the study was stopped early because of safety issues in the tasisulam arm, tasisulam was considered unlikely to be superior to paclitaxel, and paclitaxel activity in the second-line treatment of melanoma was much lower than expected. The toxicity imbalance was attributed to an unexpectedly low tasisulam clearance in a subset of patients, underscoring the importance of pharmacokinetic monitoring of compounds with complex dosing, even in late-phase studies.
authors.affiliation: The Angeles Clinic and Research Institute, Los Angeles, California.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.forename: Robert
authors.initials: R
authors.lastname: Ilaria
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Pascal
authors.initials: P
authors.lastname: Wolter
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Ana
authors.initials: A
authors.lastname: Arance
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.forename: Marjo
authors.initials: M
authors.lastname: Hahka-Kemppinen
authors.forename: Christopher
authors.initials: C
authors.lastname: Kaiser
authors.forename: P Kellie
authors.initials: PK
authors.lastname: Turner
authors.forename: Ilaria
authors.initials: I
authors.lastname: Conti
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000175:diagnosis; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D007970:Leukopenia / Q000139:chemically induced / Q000175:diagnosis; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary*; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012720:Severity of Illness Index; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000175:diagnosis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C534068:N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide; D013449:Sulfonamides; D017239:Paclitaxel
keywords: LY573636; clinical trial; melanoma; paclitaxel; phase 3 chemotherapy; tasisulam