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 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 and the promotion of cell proliferation [
5]. Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in a number of malignancies, including lymphoid leukemia, melanoma, glioblastoma, and cancers of the breast, ovary, lung, pancreas, colon, head and neck, cervix, and kidney [
6‐
8]. Thus, targeting components of the Notch signaling pathway may be a relevant option for cancer treatment.
Crenigacestat is a potent small molecule inhibitor of Notch cleavage that prevents the release of the Notch intracellular domain by inhibiting proteolytic activity of γ-secretase complex, and thereby decreasing Notch signaling and its downstream biologic effects. A phase 1, nonrandomized, open-label, multicenter trial that evaluated the safety and antitumor activity of crenigacestat in non-Japanese patients with advanced or metastatic cancers recommended a phase 2 dose of crenigacestat monotherapy at 50 mg administered 3 times per week (TIW) during a 28-day cycle [
9]. In the confirmatory, expansion trial of crenigacestat in patients with adenoid cystic carcinoma, it was demonstrated that crenigacestat has a manageable safety profile and a clinical pharmacodynamic effect on Notch-targeted genes. At the recommended phase 2 dose, the most frequent toxicities included diarrhea, nausea, and vomiting [
9]. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma [
9]. Crenigacestat was further explored in patients with adenoid cystic carcinoma and sarcoma [
10,
11].
In this phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, we evaluated the tolerability of crenigacestat up to the global recommended dose in Japanese patients with advanced solid tumors.
Methods
Study design
I6F-JE-JJCC was a phase 1, single- center, nonrandomized, single-arm, open-label, dose-escalation study of crenigacestat (LY3039478) in Japanese patients with advanced solid tumors (NCT02836600). The primary objective was to evaluate the tolerability of crenigacestat up to the global recommended dose in Japanese patients with advanced solid tumors. Secondary objectives were to characterize the safety and toxicity profile, to evaluate the pharmacokinetic (PK) parameters, and to document any antitumor activity of crenigacestat. This study was conducted in compliance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, International Conference on Harmonization Guidelines for Good Clinical Practice, and applicable local regulations. The ethics committees at the participating center approved the protocol, and all patients provided written informed consent before study entry.
Patients
Eligible patients were Japanese (≥20 years of age) with histological or cytological evidence of advanced and/or metastatic solid tumor for whom standard therapies failed or would not be appropriate. Patients had measurable and/or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) [
12], the Eastern Cooperative Oncology group (ECOG) performance status of ≤1, and adequate organ function. Patients discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug. Patients were excluded if they had received treatment with any study drug that had not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively. Patients were not permitted in the study if they had a serious preexisting medical condition, received prior treatment with a Notch inhibitor, had persistent bleeding, or had undergone major surgery within 28 days prior to the first dose.
Study treatment and dose escalation
The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally TIW prior to a meal. A cycle was defined as 28 days. Patients were admitted to the investigational site for 4 weeks through the entire first cycle but were discharged and managed on an outpatient basis on or after day 15 upon investigator discretion. The planned duration of treatment was not fixed. Treatment continued until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met.
Data were evaluated on an ongoing basis until the tolerability of crenigacestat for 50 mg was confirmed. Safety data, in particular adverse events (AEs), were the primary criteria for dose escalation. Dose escalation was driven for each treatment combination using the 3 + 3 method. Transition of dose level (from 25 to 50 mg) proceeded if the frequency of dose-limiting toxicity (DLT) observed in cycle 1 was <33% of patients in the first dose level (25 mg). For DLTs, an evaluable patient was defined as a patient who received ≥75% of the planned dose in cycle 1 or a patient who experienced DLT in cycle 1.
Safety assessment
Adverse events were collected throughout the study and coded using Medical Dictionary for Regulatory Activities (MedDRA) terms (Version 22.0). Dose-limiting toxicities were defined as AEs during cycle 1 that were related to crenigacestat and fulfilled any one of the following criteria using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v 4.0: CTCAE grade ≥ 3 non-hematological toxicity (exceptions made for nausea, vomiting, or constipation that lasts <72 h and can be controlled with treatment; transient grade 3 elevations of alanine aminotransferase and/or aspartate aminotransferase), CTCAE grade 4 hematological toxicity of >5 days duration, any febrile neutropenia, grade 3 thrombocytopenia with bleeding, or grade 4 thrombocytopenia, and other significant toxicity deemed to be dose limiting by the investigator. Dose-limiting equivalent toxicities (DLETs) were defined as an AE occurring in any cycle (other than cycle 1) that meets the criteria for a DLT if it had occurred during cycle 1.
Efficacy assessment
Tumor response, including overall response rate, was measured using RECIST v1.1 [
12] or the Response Assessment in Neuro-Oncology criteria for glioblastoma [
13]. Patient’s full extent of disease was also assessed via evaluation of performance status (ECOG). Where applicable, tumor measurements were performed by positron emission tomography response criteria of the European Organization for Research and Treatment of Cancer [
14], as well as evaluation of tumor markers. To confirm objective responses, all lesions were radiologically assessed and the same radiologic method used at baseline and for the initial response determination was repeated at least 4 weeks following the initial observation of an objective response.
Pharmacokinetics
All patients who received at least 1 dose of the study drug, and had sufficient samples collected, were included in the PK analysis. Samples were collected for PK analysis up to 24 h following the first dose of crenigacestat. Plasma concentrations of crenigacestat were quantified using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The PK parameters for crenigacestat were calculated by standard noncompartmental methods of analysis. The primary PK parameters for analysis were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time zero to infinity or over 1 dosing interval at steady state of crenigacestat.
Statistical analyses
Data from all patients who received at least 1 dose of crenigacestat treatment were included in the summaries of safety and efficacy. The analyses for this study were descriptive, except for possible exploratory analysis, as deemed appropriate. The sample size was determined by the study design, rather than a statistical power calculation. Continuous variables were presented using the mean, standard deviation (SD), median, minimum, maximum, and number of patients with an observation. For categorical variables, the population size, number of events, number of subjects with events, and percentage of subjects with events were reported.
Discussion
This report describes the first clinical study of crenigacestat in Japanese patients with solid tumors. Results of this phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study indicate that crenigacestat is tolerated at both the 25 mg and 50 mg doses in Japanese patients, with 50 mg TIW confirmed as the recommended phase 2 dose in this population [
9].
The duration of treatment was relatively short for both treatment arms (median treatment duration of 8 weeks and 4 weeks for 25-mg and 50-mg crenigacestat treatment arms, respectively). The majority of TEAEs were mild or moderate in intensity, and no TEAEs of grade 4 or 5 in severity were reported. Gastrointestinal disorders and toxicities (including diarrhea and vomiting) were among the most commonly reported TEAEs related to study treatment. These GI toxicities were manageable, and none led to study discontinuation. This is consistent with previously reported dose escalation and other dose expansion cohorts of crenigacestat [
9‐
11]. The PK profile of crenigacestat observed in this study was generally consistent with PK data reported in global phase 1 studies [
9‐
11].
There were no partial or complete responses to treatment in Japanese patients at either the 25 mg or 50 mg doses of crenigacestat, and the majority of patients exhibited progressive disease. Similar to the current report, a recent phase 1 study of crenigacestat demonstrated manageable toxicity and limited clinical activity, with no confirmed responses, in patients with adenoid cystic carcinoma [
10]. However, we observed one female patient (age 36 years) in the 50-mg treatment arm with stable disease for 22.5 months and tumor shrinkage of 22.4%. This patient had a desmoid tumor (aggressive fibromatosis), which is clinically important as there are currently no established or evidence-based treatment options available for this disease. This patient was enrolled in the current study because the mode of action of crenigacestat is predicted to be effective in the treatment of desmoid tumors. Desmoid tumors are often locally aggressive and are driven by aberrations within the WNT/β-catenin pathway [
15,
16]. Along with overexpression of β-catenin, desmoid tumors have been shown to highly express
NOTCH1 and its downstream transcription factor
HES1 [
17].
Interestingly, the Notch pathway is thought to be a therapeutic target for these tumors [
15,
16]. Antitumor activity by single agents targeting the Notch signaling pathway, such as a γ-secretase inhibitor and a monoclonal antibody targeting Notch 2/3 receptors, have been observed in early phase clinical trials of sarcoma or desmoid tumors [
11,
18‐
23]. Hence, there is potential for the use of crenigacestat and other inhibitors of the Notch signaling pathway in the treatment of sarcoma.
Limitations of this study were the small sample size and the nonrandomized, single-arm study design, although this is typical of dose-escalation studies. Overall, crenigacestat monotherapy and other notch inhibitors have shown modest or limited activity in early phase trials of solid tumors. Exploration of potential predictive biomarkers to identify patients most likely to benefit from Notch monotherapy is warranted. Trials focusing on non-solid tumors, such multiple myeloma, are being explored due to the modulation of BCMA by γ-secretase inhibitors. Future evaluation of crenigacestat in Japanese patients may be warranted.
Conclusions
Overall, crenigacestat was tolerated at both the 25 mg and 50 mg doses in Japanese patients with solid tumors. However, no clinical activity of crenigacestat was observed at the recommended dose in this patient population, and there was no confirmed objective response during the observation period of this study.
Acknowledgments
The authors would like to thank all study participants, their families, and caregivers. This study was funded by Eli Lilly and Company. Medical writing and editorial assistance was provided by Lisa Cossens and Cynthia Rae Abbott from Syneos Health and funded by Eli Lilly Japan K.K.
Compliance with ethical standards
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