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A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors
Open accessAbstract
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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Two additional, entirely distinct classes of small-molecule molecular glue degraders have been discovered.
“Two additional, entirely distinct classes of small-molecule molecular glue degraders have been discovered.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [177]
RBM39 (CAPERα) is the direct molecular target responsible for the antitumour effect of aryl sulfonamides, which recruit RBM39 to CRL4DCAF15 for polyubiquitination and proteasomal degradation.
“Two independent groups identified RNA-binding motif protein 39 (RBM39, also known as CAPERα), a nuclear protein involved in pre-mRNA splicing, as the direct molecular target responsible for the antitumour effect of these sulfonamides, which recruit this splicing factor to the CRL4DCAF15 E3 ubiquitin ligase for polyubiquitination and subsequent proteasomal degradation177–179.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [177]
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“9%).(4) This led to the implementation of a lean body-weight–based(5) dosing paradigm that reduced pharmacokinetic variability and led to the determination of the maximum tolerated dose of tasisulam, with a C max target of 420 g/ml, which was brought forward into the phase-II program.”
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“Consistent with recent findings [15], tasisulam was found to have a bi-exponential disposition pattern with a predicted distribution half-life ranging from 0.”
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“Subsequent pharmacokinetics/toxicity modeling analyses identified pre-cycle serum albumin as an important factor for minimizing the risk of hematologic toxicity [6].”
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“With respect to antitumor agents, Ly573636-sodium (tasisulam) is an antitumor small molecule with a novel mechanism of action that is being evaluated in clinical trials in multiple cancer types, melanoma, lung cancer, and refractory solid tumors [55].”
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Metadata
- Authors
- Simon, G. R., Ilaria, R. L., 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.
- Affiliations
- Medical University of South Carolina (US)
- Eli Lilly (United States) (US)
- Memorial Sloan Kettering Cancer Center (US)
- Moffitt Cancer Center (US)
- Corresponding author
- Simon, George R.
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 2011-03-23
- Volume
- 68
- Issue
- 5
- Pages
- 1233-1241
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- PMC
- PMC3215883
- OpenAlex
- W2100483340
- Cited by
- 19
- References
- 20
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2021: 1 · 2020: 2 · 2017: 2 · 2015: 2 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- refractory solid tumors, lean body weight, pharmacokinetics, albumin binding, dose-limiting toxicity, hematologic toxicity, loading dose, chronic dosing, targeted anticancer agents
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Algorithms, Antineoplastic Agents, Benzamides, Chromatography, Liquid, Female, Half-Life, Humans, Male, Middle Aged, Neoplasms, Sulfonamides, Reproducibility of Results, Maximum Tolerated Dose, Tandem Mass Spectrometry, Young Adult
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