TY - JOUR
T1 - A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma
AU - De Jesus-Acosta, Ana
AU - Laheru, Daniel
AU - Maitra, Anirban
AU - Arcaroli, John
AU - Rudek, Michelle A.
AU - Dasari, Arvind
AU - Blatchford, Patrick J.
AU - Quackenbush, Kevin
AU - Messersmith, Wells
N1 - Funding Information:
Funding This research was supported by the Lustgarten Foundation Correlative Study Grant Application (WAM, AM, MAR); NIH/NCI grant U01 CA070095 (MAR); Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005; Shared Instrument Grant (1S10RR026824-01); and the Genomics Core at the University of Colorado Cancer Center (P30-CA046934). This publication was made possible in part by Grant Number UL1RR025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Funding Information:
This study, sponsored by the U.S. National Cancer Institute/ Cancer Therapy Evaluation Program, was conducted to explore the efficacy of RO4929097 in second-and third-line metastatic pancreatic cancer. The Notch pathway has been shown to be important in pancreatic cancer initiation, progression and maintenance [6, 12]. Authors within our group have previously shown over-expression of the Notch receptors 1, 2 and 4 in 40, 20 and 25 % respectively within a panel of 20 human pancreatic cancer cell lines. Ligand-dependent activation of the Notch pathway, through overexpression of JAG2 and DLL4 ligands, resulted in over-expression of Notch-target genes Hes-1 (80 %) and Hey2 (65 %). Furthermore, overex-pression of a constitutively active Notch intracytoplasmic domain in a pancreatic cell line resulted in enhanced growth potential, whereas using a γ-secretase inhibitor or siRNA to inhibit the pathway diminished the malignant phenotype [12].
PY - 2014/8
Y1 - 2014/8
N2 - Purpose: The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA). Methods: A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses. Results: Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration. Conclusions: RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.
AB - Purpose: The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA). Methods: A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses. Results: Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration. Conclusions: RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.
KW - Gamma secretase inhibitor
KW - Notch signaling
KW - Pancreatic cancer
KW - Pharmacokinetics
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U2 - 10.1007/s10637-014-0083-8
DO - 10.1007/s10637-014-0083-8
M3 - Article
C2 - 24668033
AN - SCOPUS:84904550068
SN - 0167-6997
VL - 32
SP - 739
EP - 745
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 4
ER -