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A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer
Shubham Pant1, Suzanne F Jones2, Carla D Kurkjian1
1Stephenson Cancer Center University of Oklahoma, Oklahoma City, OK, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
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.
Insights
This phase I trial found that 30 mg of LY900009, a Notch signaling inhibitor, is the recommended dose for future studies. Adverse events included diarrhea and vomiting, with dose-limiting toxicity at higher amounts.
Area of Science:
- Oncology
- Pharmacology
- Cell Signaling
Background:
- Notch signaling is crucial for stem cell development and survival, and its dysregulation is implicated in various cancers.
- LY900009 is an oral small molecule inhibitor targeting the gamma-secretase protein to disrupt Notch signaling.
- This study presents the first-in-human Phase I clinical trial data for LY900009.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) of LY900009 in patients with advanced cancers.
- To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY900009.
- To assess the preliminary antitumour activity of LY900009.
Main Methods:
- A dose escalation (Part A) and dose confirmation (Part B) study design was employed.
- Patients received LY900009 orally three times weekly for 28-day cycles.
- The primary endpoint was MTD, with secondary endpoints including toxicity, pharmacokinetics, pharmacodynamics, and antitumour response.
Main Results:
- Thirty-five patients were treated with LY900009 doses ranging from 2-60 mg.
- Common adverse events included diarrhea (46%), vomiting (34%), and anorexia (31%).
- A dose-limiting toxicity of grade III mucosal inflammation was observed at 30 mg. LY900009 demonstrated dose-dependent inhibition of plasma amyloid-beta peptide levels (80-90% at 30-60 mg). Five patients achieved stable disease, and two completed four cycles of therapy.
Conclusions:
- The recommended MTD for LY900009 in future studies is 30 mg thrice weekly.
- This dose level exceeds preclinical target inhibition levels, suggesting potential for tumor regression in humans.
- LY900009 shows a manageable safety profile and pharmacodynamic activity, warranting further investigation in cancer patients.
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