A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors Journal Article
| Authors: | Simon, G. R.; Ilaria, R. L. Jr; Sovak, M. A.; Williams, C. C.; Haura, E. B.; Cleverly, A. L.; Sykes, A. K.; Wagner, M. M.; De Alwis, D. P.; Slapak, C. A.; Miller, M. A.; Spriggs, D. R. |
| Article Title: | 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). |
| Keywords: | adult; controlled study; aged; major clinical study; area under the curve; diarrhea; dose response; drug withdrawal; gastrointestinal hemorrhage; side effect; solid tumor; chemotherapy; binding affinity; multiple cycle treatment; ovary cancer; blood toxicity; leukopenia; lung non small cell cancer; stomatitis; thrombocytopenia; antineoplastic activity; cancer resistance; drug dose escalation; febrile neutropenia; loading drug dose; pneumonia; drug fatality; hypokalemia; prothrombin time; drug antagonism; albumin; drug mechanism; multicenter study; spinal cord compression; warfarin; thrombocyte count; drug clearance; pancytopenia; maximum plasma concentration; drug blood level; leukocyte count; maximum tolerated dose; phase 1 clinical trial; drug half life; thymoma; drug protein binding; solid tumors; adult respiratory distress syndrome; hemoptysis; phase i; lung hemorrhage; turnover time; ly573636; tasisulam; lean body weight |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 68 |
| Issue: | 5 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2011-11-01 |
| Start Page: | 1233 |
| End Page: | 1241 |
| Language: | English |
| DOI: | 10.1007/s00280-011-1593-0 |
| PROVIDER: | scopus |
| PMCID: | PMC3215883 |
| PUBMED: | 21431416 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 January 2012" - "CODEN: CCPHD" - "Source: Scopus" |
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