A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer. (March 2016)

• Record Type: Journal Article
• Authors: Pant, Shubham; Jones, Suzanne F.; Kurkjian, Carla D.; Infante, Jeffrey R.; Moore, Kathleen N.; Burris, Howard A.; McMeekin, Donald S.; Benhadji, Karim A.; Patel, Bharvin K.R.; Frenzel, Martin J.; Kursar, Jonathan D.; Zamek-Gliszczynski, Maciej J.; Yuen, Eunice S.M.; Chan, Edward M.; Bendell, Johanna C.
• Is Part Of: European journal of cancer. Volume 56(2016)
• Page Start: 1
• Page End: 9
• Publication Date: 2016-03
• Subjects: Notch -- Advanced cancer -- Gamma secretase -- LY900009; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2015.11.021
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Notch signalling regulates stem cell development and survival and is deregulated in multiple malignancies. LY900009 is a small molecule inhibitor of Notch signalling via selective inhibition of the γ-secretase protein. We report the first-in-human phase I trial of LY900009. Methods: Dose escalation (Part A) was performed in cohorts of three advanced cancer patients using a modified continual reassessment method and dose confirmation (Part B) was performed in ovarian cancer patients. LY900009 was taken orally thrice weekly (every Monday, Wednesday, and Friday) during a 28-d cycle. The primary objective determined the maximum tolerated dose (MTD); secondary end-points included toxicity, pharmacokinetics, pharmacodynamics, and antitumour activity. Results: Thirty-five patients received LY900009 at dose levels ranging from 2–60 mg. Study drug-related adverse events were diarrhoea (46%), vomiting (34%), anorexia (31%), nausea (31%), and fatigue (23%). At 30 mg, a dose-limiting toxicity (grade III mucosal inflammation) was observed. LY900009 absorption was rapid, with median tmax at 1–4 h post-dose. LY900009 inhibited plasma levels of amyloid-β peptide in a dose-dependent manner with 80–90% inhibition observed in the 30- to 60-mg cohorts. No responses were seen, but five patients had stable disease. Two patients (5.7%) with leiomyosarcoma and ovarian cancer received four cycles of therapy. One patient (15 mg) showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. Conclusions: The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans. Highlights: LY900009 was tolerable, with no unexpected safety concerns being reported. LY900009 absorption was rapid (median t max approximately 1–4 h post-dose). A maximum tolerated dose of 30 mg thrice weekly was established. Antitumour activity was limited; 14% of patients achieved stable disease.