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A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.

ABSTRACT: The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the ?-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).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.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.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.

SUBMITTER: De Jesus-Acosta A

PROVIDER: S-EPMC4292847 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.

De Jesus-Acosta Ana A Laheru Daniel D Maitra Anirban A Arcaroli John J Rudek Michelle A MA Dasari Arvind A Blatchford Patrick J PJ Quackenbush Kevin K Messersmith Wells W

Investigational new drugs 20140327 4

<h4>Purpose</h4>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).<h4>Methods</h4>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- ...[more]

PMID: 24668033

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Project description:PRECLINICAL STUDIES: have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) STUDY OBJECTIVES: To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer RESULTS: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination CONCLUSIONS: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.

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A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.

Publications

A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.

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