PURPOSE: In this phase I trial in humans the safety and pharmacology of LY309887 on a weekly schedule combined with daily oral 5-mg doses of folic acid were evaluated. BACKGROUND: LY309887 is an inhibitor of folate-dependent enzymes involved in de novo purine biosynthesis and has a broad preclinical antitumor activity. In murine systems, combining this agent with exogenous folic acid results in an enhanced therapeutic index. METHODS: This study was a single-institution, open-label, clinical trial of dose escalation with toxicity and pharmacokinetic parameters determined. The dose range studied was 0.5-4 mg/m2 per week x6 and then a modified schedule weekly x3 every 6 weeks. RESULTS: Dose-limiting toxicities were of delayed onset and associated with hematologic, neurologic, and mucosal effects. Pharmacokinetic parameters revealed dose linearity for AUC and Cmax. Low circulating levels of drug persisted for over 200 h. Urinary excretion accounted for approximately 50% of the parent drug but was highly variable. The urinary excretion was near maximal within 24 h of dosing. CONCLUSIONS: The modified dosing schedule allowed repetitive dosing in patients. Further evaluation of the 2 mg/m2 per week x3 every 6 weeks with daily oral folate supplement as a potential phase II dose may be warranted.
PURPOSE: In this phase I trial in humans the safety and pharmacology of LY309887 on a weekly schedule combined with daily oral 5-mg doses of folic acid were evaluated. BACKGROUND:LY309887 is an inhibitor of folate-dependent enzymes involved in de novo purine biosynthesis and has a broad preclinical antitumor activity. In murine systems, combining this agent with exogenous folic acid results in an enhanced therapeutic index. METHODS: This study was a single-institution, open-label, clinical trial of dose escalation with toxicity and pharmacokinetic parameters determined. The dose range studied was 0.5-4 mg/m2 per week x6 and then a modified schedule weekly x3 every 6 weeks. RESULTS: Dose-limiting toxicities were of delayed onset and associated with hematologic, neurologic, and mucosal effects. Pharmacokinetic parameters revealed dose linearity for AUC and Cmax. Low circulating levels of drug persisted for over 200 h. Urinary excretion accounted for approximately 50% of the parent drug but was highly variable. The urinary excretion was near maximal within 24 h of dosing. CONCLUSIONS: The modified dosing schedule allowed repetitive dosing in patients. Further evaluation of the 2 mg/m2 per week x3 every 6 weeks with daily oral folate supplement as a potential phase II dose may be warranted.
Authors: Lei Wang; Adrianne Wallace; Sudhir Raghavan; Siobhan M Deis; Mike R Wilson; Si Yang; Lisa Polin; Kathryn White; Juiwanna Kushner; Steven Orr; Christina George; Carrie O'Connor; Zhanjun Hou; Shermaine Mitchell-Ryan; Charles E Dann; Larry H Matherly; Aleem Gangjee Journal: J Med Chem Date: 2015-08-28 Impact factor: 7.446
Authors: Lei Wang; Sita Kugel Desmoulin; Christina Cherian; Lisa Polin; Kathryn White; Juiwanna Kushner; Andreas Fulterer; Min-Hwang Chang; Shermaine Mitchell-Ryan; Mark Stout; Michael F Romero; Zhanjun Hou; Larry H Matherly; Aleem Gangjee Journal: J Med Chem Date: 2011-09-22 Impact factor: 7.446
Authors: Robert Pejchal; Elizabeth Campbell; Brian D Guenther; Brett W Lennon; Rowena G Matthews; Martha L Ludwig Journal: Biochemistry Date: 2006-04-18 Impact factor: 3.162
Authors: Lei Wang; Christina Cherian; Sita Kugel Desmoulin; Lisa Polin; Yijun Deng; Jianmei Wu; Zhanjun Hou; Kathryn White; Juiwanna Kushner; Larry H Matherly; Aleem Gangjee Journal: J Med Chem Date: 2010-02-11 Impact factor: 7.446
Authors: Lalit K Golani; Adrianne Wallace-Povirk; Siobhan M Deis; Jennifer Wong; Jiyuan Ke; Xin Gu; Sudhir Raghavan; Mike R Wilson; Xinxin Li; Lisa Polin; Parker W de Waal; Kathryn White; Juiwanna Kushner; Carrie O'Connor; Zhanjun Hou; H Eric Xu; Karsten Melcher; Charles E Dann; Larry H Matherly; Aleem Gangjee Journal: J Med Chem Date: 2016-08-26 Impact factor: 7.446