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Clinical Trial
. 2015 Sep;26(9):1923-1929.
doi: 10.1093/annonc/mdv264. Epub 2015 Jun 19.

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

B H O'Neil  1 , A J Scott  2 , W W Ma  3 , S J Cohen  4 , D L Aisner  2 , A R Menter  5 , M A Tejani  6 , J K Cho  7 , J Granfortuna  8 , L Coveler  9 , O O Olowokure  10 , J C Baranda  11 , M Cusnir  12 , P Phillip  13 , J Boles  14 , R Nazemzadeh  15 , M Rarick  16 , D J Cohen  17 , J Radford  18 , L Fehrenbacher  19 , R Bajaj  20 , V Bathini  21 , P Fanta  22 , J Berlin  23 , A J McRee  24 , R Maguire  25 , F Wilhelm  25 , M Maniar  25 , A Jimeno  2 , C L Gomes  26 , W A Messersmith  27
Affiliations
Clinical Trial

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

B H O'Neil et al. Ann Oncol. 2015 Sep.

Erratum in

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.

Keywords: PI3K inhibitor; PLK1 inhibitor; Ras mimetic; pancreatic cancer; phase II/III; rigosertib.

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Figures

Figure 1.
Figure 1.
CONSORT diagram.
Figure 2.
Figure 2.
(a) OS Kaplan–Meier estimates of OS ITT population (n = 160). (b) PFS Kaplan–Meier estimates of PFS ITT population (n = 160).
Figure 3.
Figure 3.
Mutation analysis—41 samples positive for a mutation.
See this image and copyright information in PMC

References

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