A Phase I Clinical Trial of Spicamycin Derivative KRN5500 (NSC 650426) Using a Phase I Accelerated Titration “2B” Design

Abstract

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m2/d x 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m2/d x 5. The recommended Phase II dose i s 4.3mg/m2/d x 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8-8.4 mg/m2/d x 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.

Liquid chromatography and tandem mass spectrometry for the quantitative determination of ixabepilone (BMS-247550, Ixempra™) in human plasma: Method validation, overcoming curve splitting issues and eliminating chromatographic interferences from degradants

“…The objective was to develop and validate a simple, rapid, sensitive, and specific LC-MS/MS analytical method for the measurement of ixabepilone concentrations in human plasma. Quantitation methods were briefly described in two published Phase I clinical trials [7,8], however, this article presents the method development and validation in more detail. Ixabepilone drug substance is insoluble in water at 25 • C. The pH of a saturated solution of ixabepilone in water ranges from 6.6 to 7.1.…”

Theoretical and Practical Application of Traditional and Accelerated Titration Phase I Clinical Trial Designs: The Wayne State University Experience

“…Five clinical trials (5-fluoro-pyrimidinone, XK-469, SR271425, BMS247550, KRN5500) were conducted utilizing the AT design (Alousi et al, 2007; Gadgeel et al, 2003, 2005; LoRusso et al, 2002;?). Four of five agents (XK-469, SR271425, BMS247550, KRN5500) were administered intravenously using the 2B design, and the remaining agent (5-fluoro-pyrimidinone) was administered orally using the 4B design.…”

Insights into the biosynthesis of septacidin l-heptosamine moiety unveils a VOC family sugar epimerase

“…Anicemycin is an inhibitor of anchorage-independent growth of tumor cells 16 . Spicamycin displays excellent antitumor activities and one of its derivatives, KRN5500, entered phase I clinical trial as an anticancer agent and phase II clinical trial as a drug for neuropathic pain relief 17 , 18 , 19 , 20 .…”