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

Abstract

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 28-day 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.

Notch‐triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through endothelial nitric oxide synthase

“…Importantly, unlike DAPT, LY3039478 is an orally bioavailable selective Notch inhibitor that has already been administered in a phase 1 clinical trial for solid tumor treatment. [44][45][46][47] Consequently, LY3039478 is likely to be safer and closer to clinical translational use in NASH patients. Nevertheless, pharmacological Notch inhibitors such as DAPT and LY3039478 are likely to affect not only LSECs but also hepatocytes, Kupffer cells, and even HSCs, highlighting the need for the identification or development of EC-specific Notch inhibitors as potential NASH treatment options.…”

Clinical usefulness of eribulin as first- or second-line chemotherapy for recurrent HER2-negative breast cancer: a randomized phase II study (JBCRG-19)

“…A phase III comparative study (study 305) reported that eribulin improved OS of patients with previously treated metastatic breast cancer compared with TPC [ 15 ]. In Japan, an observational study concluded that eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer [ 16 ]. The real-world observational ESME program enrolling 16,703 metastatic breast cancer patients evaluated outcomes of patients treated with eribulin as second-, third- and fourth-line treatment and found a significant improvement in OS and PFS compared with other chemotherapies for all lines among the HER2-negative patient subgroup [ 17 ].…”

The Notch signaling pathway: a potential target for cancer immunotherapy

“…11 patients had stable disease. The most common toxicities included: fatigue (82%; grade 36%), mucositis, (71%;), neutropenia (59%), anemia (59%), and hypertriglyceridemia (59%) NCT01218620; I Adult solid neoplasm 2010; Completed; USA Unpublished LY3039478 γ-secretase inhibitor NCT02836600 [ 56 ]; I Advanced solid tumor 2016; Active, not recruiting; Japan In 11 enrolled Japanese patients, no dose-limiting toxicities or dose-limiting equivalent toxicities were observed. 1 patient (14.3%) with a desmoid tumor showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months.…”