A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

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PHASE I STUDIES

A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors Toshihiko Doi 1

&

Masaomi Tajimi 2 & Joji Mori 2 & Hiroya Asou 2 & Koichi Inoue 2 & Karim A. Benhadji 3 & Yoichi Naito 1

Received: 30 July 2020 / Accepted: 9 September 2020 # The Author(s) 2020

Summary Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW. Trial registration: NCT02836600 (ClinicalTrials.gov) registered on July 19, 2016. Keywords Crenigacestat . Japanese . LY3039478 . Notch pathway . Phase 1 . Solid tumor

Introduction The Notch signaling pathway is evolutionarily conserved in mammals and plays an important role in cell development and differentiation [1]. In mammals, there are four isoforms of Notch receptors (Notch-1, Notch-2, Notch-3, and Notch-4) [2] and five Notch ligands (Dll-1, Dll-3, Dll-4, Jagged-1, and Jagged-2) [3], which are vital in mediating

* Toshihiko Doi [email protected] 1

National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa-shi, Chiba 277-8577, Japan

2

Eli Lilly Japan K.K, Kobe, Japan

3

Eli Lilly and Company, New York, NY, USA

communication between adjacent cells expressing these receptors and ligands [4]. A substantial body of evidence suggests that Notch signaling plays important oncogenic roles in several types of cancer [4]. The oncogenic functions of Notch signaling include the inhibition of apoptosis a