A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer
Shubham Pant, Suzanne F Jones, Carla D Kurkjian, Jeffrey R Infante, Kathleen N Moore, Howard A Burris, Donald S McMeekin, Karim A Benhadji, Bharvin K R Patel, Martin J Frenzel, Jonathan D Kursar, Maciej J Zamek-Gliszczynski, Eunice S M Yuen, Edward M Chan, Johanna C Bendell, Shubham Pant, Suzanne F Jones, Carla D Kurkjian, Jeffrey R Infante, Kathleen N Moore, Howard A Burris, Donald S McMeekin, Karim A Benhadji, Bharvin K R Patel, Martin J Frenzel, Jonathan D Kursar, Maciej J Zamek-Gliszczynski, Eunice S M Yuen, Edward M Chan, Johanna C Bendell
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.
Trial registration: ClinicalTrials.gov NCT01158404.
Keywords: Advanced cancer; Gamma secretase; LY900009; Notch.
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Source: PubMed