A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

Abstract

BACKGROUND:

Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma.

MATERIALS AND METHODS:

Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM).

RESULTS:

A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected.

CONCLUSIONS:

The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

• Authors: B H O'Neil, A J Scott, W W Ma, S J Cohen, D L Aisner, A R Menter, M A Tejani, J K Cho, J Granfortuna, L Coveler, O O Olowokure, J C Baranda, M Cusnir, P Phillip, J Boles, R Nazemzadeh, M Rarick, D J Cohen, J Radford, L Fehrenbacher, R Bajaj, V Bathini, P Fanta, J Berlin, A J McRee, R Maguire, F Wilhelm, M Maniar, A Jimeno, C L Gomes, W A Messersmith
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 26 Issue 9 Pg. 1923-1929 (09 2015) ISSN: 1569-8041 [Electronic] England
• PMID: 26091808 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Antimetabolites, Antineoplastic
• Cell Cycle Proteins
• KRAS protein, human
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins
• Sulfones
• TP53 protein, human
• Tumor Suppressor Protein p53
• Deoxycytidine
• ON 01910
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Protein Serine-Threonine Kinases
• polo-like kinase 1
• Proto-Oncogene Proteins p21(ras)
• Glycine
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy)
• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Cycle Proteins (antagonists & inhibitors)
• Class I Phosphatidylinositol 3-Kinases
• Deoxycytidine (adverse effects, analogs & derivatives, therapeutic use)
• Disease-Free Survival
• Drug Administration Schedule
• Female
• Glycine (adverse effects, analogs & derivatives, therapeutic use)
• Humans
• Male
• Middle Aged
• Pancreatic Neoplasms (drug therapy)
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Sulfones (adverse effects, therapeutic use)
• Tumor Suppressor Protein p53 (genetics)
• Gemcitabine