A first-in-human phase I study of the oral Notch inhibitor LY900009 in patients with advanced cancer

Autor: Emma Jones, Carla Kurkjian, Maciej J. Zamek-Gliszczynski, Eunice Yuen, Johanna C. Bendell, D. Scott McMeekin, Suzanne F. Jones, Howard A. Burris, Shubham Pant, Edward M. Chan, J D Kursar, Kathleen N. Moore, Jeffrey R. Infante
Rok vydání: 2012
Předmět:
Zdroj: Journal of Clinical Oncology. 30:3008-3008
ISSN: 1527-7755
0732-183X
Popis: 3008 Background: Notch signaling plays a critical role during stem cell self-renewal and is deregulated in multiple human cancers. The Notch pathway may be activated inappropriately by receptor mutation and overexpression as well as aberrant signals from the tumor microenvironment. LY900009 is a selective small-molecule inhibitor of gamma secretase, the enzyme that cleaves and thereby activates Notch receptors. Methods: Dose escalation was performed in cohorts of 3 patients (pts) using a modified continual reassessment method. LY900009 was taken orally thrice weekly (every MWF) during a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and clinical endpoints were evaluated. Results: 22 patients received LY900009 across 6 dose levels: 2mg (3pts), 4mg (4pts), 8mg (3pts), 15mg (3pts), 30mg (6pts), and 60mg (3pts). The most common treatment emergent adverse events possibly related to LY900009 across all grades included diarrhea (27%), vomiting (23%), nausea (18%), fatigue (23%), anorexia (23%), hypophosphatemia (14%), and rash (18%). Dose-limiting toxicities of fatigue/N/V (G3) and diarrhea (G3) were seen in 2 patients, respectively, treated at 60mg. The maximum tolerated dose (MTD) was tentatively identified at 30mg. After a single dose, mean Cmax increased from 4 to 158 ng/ml and mean AUC0-t(last) increased from 14 to 1160 ng-hr/ml. Both Cmax and AUC0-t(last) increased in a dose-dependent manner. Elimination half-life of LY900009 was approximately 2-3 hrs. LY900009 inhibited plasma levels of amyloid-β peptide (a downstream product of gamma secretase) in a dose-dependent manner with 80-90% inhibition observed in the 30 and 60mg cohorts. In the 15mg cohort, one patient had colonic biopsy that showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. Two patients (10%) with leiomyosarcoma and ovarian cancer received 4 cycles of therapy. Conclusions: LY900009 demonstrates acceptable safety and pharmacokinetics in patients with advanced cancer. Pharmacodynamic endpoints show pathway inhibition at tolerable doses. One more cohort at 45mg is ongoing to refine the MTD and will be followed by an expansion cohort for patients with ovarian cancer.
Databáze: OpenAIRE
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