A phase i study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors

Abstract

Purpose: 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. Conclusion: 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. © 2011 The Author(s).