A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma

Cancer. 2014 Jul 1;120(13):2016-24. doi: 10.1002/cncr.28635. Epub 2014 Mar 26.

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.

Keywords: LY573636; clinical trial; melanoma; paclitaxel; phase 3 chemotherapy; tasisulam.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Benzamides / administration & dosage
  • Benzamides / adverse effects
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use*
  • Chemotherapy-Induced Febrile Neutropenia / diagnosis
  • Disease-Free Survival
  • Drug Administration Schedule
  • Early Termination of Clinical Trials*
  • Female
  • Follow-Up Studies
  • Humans
  • Kaplan-Meier Estimate
  • Leukopenia / chemically induced
  • Leukopenia / diagnosis
  • Male
  • Melanoma / drug therapy*
  • Melanoma / secondary*
  • Middle Aged
  • Neoplasm Staging
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / therapeutic use*
  • Severity of Illness Index
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology*
  • Sulfonamides / administration & dosage
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use*
  • Thrombocytopenia / chemically induced
  • Thrombocytopenia / diagnosis
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Benzamides
  • N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide
  • Sulfonamides
  • Paclitaxel