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

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-ß 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.

Can pentylenetetrazole and maximal electroshock rodent seizure models quantitatively predict antiepileptic efficacy in humans?

PURPOSE: Pentylenetetrazole and maximal electroshock rodent seizure models are commonly used to detect antiepileptic efficacy in drug development. The aim of this research was to evaluate the predictive capabilities of pentylenetetrazole and maximal electroshock models in estimating human exposures required for antiepileptic efficacy through a survey of current literature. METHODS: A literature search was undertaken to identify articles describing pentylenetetrazole or maximal electroshock models in rat or mice, where at least one of nine pre-selected antiepileptic drugs based on evidence of efficacy were used. Exposures at the median doses of the approved human dose range for these drugs were compared to exposures at doses that inhibit maximal response by 50% (ED50s) from the pentylenetetrazole and maximal electroshock models. Ratios of the human to rodent exposures were calculated and summarised statistically and graphically. RESULTS: Across the nine antiepileptic drugs investigated, the average (standard deviation) ratio of exposures comparing the median human efficacious dose to mice ED50 dose was 1.4 (3.9) for the pentylenetetrazole model and 3.8 (3.1) for the maximal electroshock model. In the rat, ratios in the maximal electroshock and pentylenetetrazole model were 4.1 (2.1) and a range of 1-2, respectively. CONCLUSION: Based on the nine antiepileptic drugs investigated, the pentylenetetrazole model appeared to predict human exposures more accurately than the maximal electroshock model. There did not appear to be differences between rat and mice in either of the seizure models, therefore both species could be used equally. Both the pentylenetetrazole and maximal electroshock models are useful tools in screening compounds in early drug discovery.

How predictive are photosensitive epilepsy models as proof of principle trials for epilepsy?

PURPOSE: Human photosensitive epilepsy models have been used as proof of principle (POP) trials for epilepsy. Photosensitive patients are exposed to intermittent photic stimulation and the reduction in sensitivity to the number of standard visual stimulation frequencies is used as an endpoint. The aim of this research was to quantify the predictive capabilities of photosensitive POP trials, through a survey of current literature. METHODS: A literature search was undertaken to identify articles describing photosensitive POP trials. Minimally efficacious doses (MEDs) in epilepsy were compared to doses in the POP trials that produced 50-100% response (ED50-100). Ratios of these doses were calculated and summarised statistically. RESULTS: The search identified ten articles describing a total of 17 anti-epileptic drugs. Of these, data for both MED and ED50-100 were available for 13 anti-epileptic drugs. The average ratio of MED to ED50-100 was 0.95 (95% CI 0.60-1.30). The difference in MED to ED50-100 ratios between partial epilepsy (0.82) was not significantly different from that of generalised epilepsy (1.08) (p=0.51). CONCLUSION: Photosensitive POP trials are a useful tool to quantitatively predict efficacy in epilepsy, and can be useful as early and informative indicators in anti-epileptic drug discovery and development.