Notch pathway inhibition with crenigacestat (LY3039478) in a phase I first-in-human clinical trial for patients with relapsed or refractory non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia

Abstract

Background: Deregulated Notch signaling is implicated in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed or refractory NHL or CLL. Objectives: This phase I clinical trial assessed the safety and efficacy of crenigacestat in patients with relapsed or refractory NHL and CLL. The main objectives were to characterize the safety profile, to confirm the recommended phase II dose of crenigacestat in patients with hematological malignancies, and to assess preliminary antitumor activity. Design: A phase I trial enrolling patients with relapsed or refractory NHL and CLL, with Notch tumor alteration based on molecular or immunohistochemistry tumor pre-screening. Methods: Eligible patients received crenigacestat 50 mg orally three times per week, for a 28-day cycle, until disease progression or unacceptable toxicity. Tumor responses were assessed using the Revised Response Criteria for Malignant Lymphoma and the National Cancer Institute Working Group for CLL. Results: Overall, 62 patients (40 with NHL and 22 with CLL) were pre-screened for a Notch alteration. Notch alteration was identified in 21/62 (34%) of patients pre-screened. Nine patients (five with peripheral T-cell NHL and three with CLL) with Notch alteration were eligible for the clinical trial and treated. The most common adverse events in all grades of severity were diarrhea (56%), nausea (56%), platelet count decrease (44%), and fatigue (33%). One patient (11%) with peripheral T-cell lymphoma obtained a partial response. Conclusion: Crenigacestat demonstrated a modest clinical activity at the recommended dose in adult patients with relapsed or refractory NHL or CLL. Trial registration: NCT01695005.