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

Nov 2011

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.

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

George R. Simon 0 1 2 3 4 5 6 Robert L. Ilaria Jr. 0 1 2 3 4 5 6 Mika A. Sovak 0 1 2 3 4 5 6 Charles C. Williams 0 1 2 3 4 5 6 Eric B. Haura 0 1 2 3 4 5 6 Ann L. Cleverly 0 1 2 3 4 5 6 Amanda K. Sykes 0 1 2 3 4 5 6 Margaret M. Wagner 0 1 2 3 4 5 6 Dinesh P. de Alwis 0 1 2 3 4 5 6 Christopher A. Slapak 0 1 2 3 4 5 6 Mary A. Miller 0 1 2 3 4 5 6 David R. Spriggs 0 1 2 3 4 5 6 0 R. L. Ilaria Jr. M. M. Wagner C. A. Slapak M. A. Miller Eli Lilly and Company, Indianapolis, IN, USA 1 G. R. Simon C. C. Williams E. B. Haura H. Lee MoYtt Cancer Center , Tampa, FL, USA 2 This study was presented in part at the 43rd American Society of Clinical Oncology Annual Meeting , June 1-5, 2007, Chicago, IL ; the 16th European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research Annual Symposium on Molecular Targets and Cancer Therapeutics , Sept. 28-Oct. 1, 2004, Geneva, Switzerland ; and the 22nd European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research Annual Symposium on Molecular Targets and Cancer Therapeutics , Nov. 16-19, 2010, Berlin, Germany 3 Present Address: M. A. Sovak Genentech, South San Francisco, CA, USA 4 Present Address: G. R. Simon (&) The Burtschy Family Endowed Chair in Cancer Research, Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina , 96 Jonathan Lucas Street, Suite 903, MSC 635, Charleston, SC 29425-6350, USA 5 M. A. Sovak D. R. Spriggs Memorial Sloan Kettering Cancer Center , New York, NY, USA 6 A. L. Cleverly A. K. Sykes D. P. de Alwis Eli Lilly and Company, Windlesham, Surrey, UK 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 Wrst 34 were treated with a Xat dose of tasisulam of up to 2,400 mg, the dose level at which all three patients had dose-limiting toxicity (DLT). Controlling for Cmax proved important to reduce the risk of toxicity; therefore, we initially focused on identifying which parameters explained Cmax (end-of-infusion concentration) variability. Pharmacokinetic analysis indicated that Cmax negatively correlates with lean body weight (LBW). Thus, the dosing regimen was revised using a LBW-based algorithm targeting a speciWc Cmax. A loading/chronic dose paradigm was then implemented as pharmacokinetic results revealed a long terminal half-life of tasisulam, likely because of its high-aYnity albumin binding. Cmax-based dose escalation was stopped at the 420- g/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 Cmaxbased dosing regimen allowed for the recommendation of a phase II tasisulam dose (loading dose of 420 g/mL targeted Cmax with all subsequent doses administered at 65% of chronic dose given every 21 days) despite pharmacological challenges posed by high albumin binding. - Tasisulam sodium (benzamide, N-[(5-bromo-2-thienyl)sulfonyl]-2,4-dichloro-, sodium salt; hereafter referred to as tasisulam), an acylsulfonamide, is a member of a new class of antineoplastic agents [1]. An in vitro, antitumor-screening analysis conducted by the National Cancer Institute (NCI COMPARE analysis) [2] demonstrated a broad range of activity for tasisulam in 60 tumor cell lines including leukemia, melanoma, non-small cell lung (NSCLC), colon, ovarian, renal, and breast cancers. In addition, the activity proWle of tasisulam in the COMPARE analysis did not match that of any other known anticancer compound [2], which suggests a mechanism of action for tasisulam that is distinct from currently available agents. Preclinical in vitro studies indicate that tasisulam induces apoptosis in cancer cells by the mitochondrial (intrinsic) cell death pathway [3], and also induces a block at the G2/M phase of the cell cycle. However, the precise cellular or mitochondrial target that leads to the induction of apoptosis remains unknown. Tasisulam has also demonstrated anti-angiogenic activity in vitro (Lilly data on Wle). In vivo pharmacokinetic studies in rats and dogs indicate that tasisulam is metabolized primarily by the liver, and has low total plasma clearance with a relatively long half-life (approximately 10 h in rats and 20 h in dogs). In vitro measurements also showed that tasisulam is highly protein bound (99%) in humans, mice, rats, and dogs (Lilly data on Wle). In addition, there was preclinical evidence of a correlation between the maximum plasma concentration (Cmax) of tasisulam and toxicity (Lilly data on Wle). The broad spectrum of preclinical antitumor activity of tasisulam and its potentially unique mechanism of action prompted this phase I dose-escalation study in patients with advanced or refractory solid tumors. The primary objective of the study was to determine the recommended phase II dose of tasisulam; secondary objectives were to characterize the toxicity and pharmacokinetic proWles of tasisulam, and to discern whether there was any antitumor activity. Patients and methods Patients 18 years of age with histologically or cytologically documented advanced and/or metastatic malignancy for which no proven eVective therapy exists were eligible to participate in this study. Patients were required to have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale, adequate bone marrow reserve, kidney and liver function. Discontinuation of all the previous therapies (including chemotherapy, radiotherapy, or other investigational therapy) at least 4 weeks before study enrollment and recovery from all toxicities were also required. Patients who had hematologic malignancies or a history of central nervous system neoplasm or who required palliative radiotherapy at study entry were excluded from study participation. Written informed consent was obtained from each patient before study participation. The study was approved by the institutional review board(s) of the participating institutions, and was conducted according to applicable laws and regulations, good clinical practices, and the ethical principles of the Declaration of Helsinki. Treatment plan and dose-escalation schema For the purpose of this open-label, single-arm, dose-escalating, phase I study, tasisulam was supplied by Eli Lilly and Company (Indianapolis, IN) in single-use, 20-mL glass vials containing tasisulam sodium, sodium chloride, and water (...truncated)


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George R. Simon, Robert L. Ilaria Jr., Mika A. Sovak, Charles C. Williams, Eric B. Haura, Ann L. Cleverly, Amanda K. Sykes, Margaret M. Wagner, Dinesh P. de Alwis, Christopher A. Slapak, Mary A. Miller, David R. Spriggs. A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors, 2011, pp. 1233-1241, Volume 68, Issue 5, DOI: 10.1007/s00280-011-1593-0