First-in-human study of LY3039478, a Notch signaling inhibitor in advanced or metastatic cancer.

2533 Background: LY3039478 (LY) is an orally bioavailable, potent, and highly selective Notch inhibitor (Notch 1-4). We report on safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of LY. Methods: Eligible pts (ECOG ≤ 1) had relapsed solid tumors, adequate hematologic, renal, and hepatic functions. Using a predictive pre-clinical PK/PD model and non-clinical toxicology data, a dose range of 2.5-100 mg was selected. LY was given three times a week (TIW) on a 28-day cycle until disease progression. Dose escalation used 3+3 design with probability toxicity band modelling. Safety assessments were based on CTCAE V4.0. Primary objective: to define the recommended phase 2 dose of LY; additional objectives: PK, PD (Aβ in plasma and a panel of 46 genes expressed in skin), and preliminary antitumor activity. Results: 55 pts were treated. The most common related toxicities ( ≥ 10% of pts) included diarrhea (42%); vomiting (40%); nausea (36%); asthenia (33%); decreased appetite (25%); hypop...