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

PURPOSE:

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: Michael S Gordon, Robert Ilaria Jr, Dinesh P de Alwis, David S Mendelson, Scott McKane, Margaret M Wagner, Katherine Y Look, Patricia M LoRusso
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 1 Pg. 21-7 (Jan 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23228983 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzamides (administration & dosage, adverse effects, pharmacokinetics)
• Bone Marrow (drug effects, pathology)
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Sulfonamides (administration & dosage, adverse effects, pharmacokinetics)