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, A. J. Scott, Wen Wee 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. FehrenbacherR. Bajaj, V. Bathini, P. Fanta, J. Berlin, A. J. McRee, R. Maguire, F. Wilhelm, M. Maniar, A. Jimeno, C. L. Gomes, Wells A. Messersmith

Research output: Contribution to journalArticle

26 Citations (Scopus)

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/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m2 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.

Original languageEnglish (US)
Article numbermdv264
Pages (from-to)1923-1929
Number of pages7
JournalAnnals of Oncology
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Fingerprint

gemcitabine
Pancreatic Neoplasms
Safety
Adenocarcinoma
Mutation
Confidence Intervals
1-Phosphatidylinositol 4-Kinase
Survival
Hyponatremia
Genetic Testing
Neutropenia
Disease-Free Survival
Anemia
ON 01910

Keywords

  • Pancreatic cancer
  • Phase II/III
  • PI3K inhibitor
  • PLK1 inhibitor
  • Ras mimetic
  • Rigosertib

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

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. / O'Neil, B. H.; Scott, A. J.; Ma, Wen Wee; Cohen, S. J.; Aisner, D. L.; Menter, A. R.; Tejani, M. A.; Cho, J. K.; Granfortuna, J.; Coveler, L.; Olowokure, O. O.; Baranda, J. C.; Cusnir, M.; Phillip, P.; Boles, J.; Nazemzadeh, R.; Rarick, M.; Cohen, D. J.; Radford, J.; Fehrenbacher, L.; Bajaj, R.; Bathini, V.; Fanta, P.; Berlin, J.; McRee, A. J.; Maguire, R.; Wilhelm, F.; Maniar, M.; Jimeno, A.; Gomes, C. L.; Messersmith, Wells A.

In: Annals of Oncology, Vol. 26, No. 9, mdv264, 01.09.2015, p. 1923-1929.

Research output: Contribution to journalArticle

O'Neil, BH, Scott, AJ, Ma, WW, Cohen, SJ, Aisner, DL, Menter, AR, Tejani, MA, Cho, JK, Granfortuna, J, Coveler, L, Olowokure, OO, Baranda, JC, Cusnir, M, Phillip, P, Boles, J, Nazemzadeh, R, Rarick, M, Cohen, DJ, Radford, J, Fehrenbacher, L, Bajaj, R, Bathini, V, Fanta, P, Berlin, J, McRee, AJ, Maguire, R, Wilhelm, F, Maniar, M, Jimeno, A, Gomes, CL & Messersmith, WA 2015, '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', Annals of Oncology, vol. 26, no. 9, mdv264, pp. 1923-1929. https://doi.org/10.1093/annonc/mdv264
O'Neil, B. H. ; Scott, A. J. ; Ma, Wen Wee ; Cohen, S. J. ; Aisner, D. L. ; Menter, A. R. ; Tejani, M. A. ; Cho, J. K. ; Granfortuna, J. ; Coveler, L. ; Olowokure, O. O. ; Baranda, J. C. ; Cusnir, M. ; Phillip, P. ; Boles, J. ; Nazemzadeh, R. ; Rarick, M. ; Cohen, D. J. ; Radford, J. ; Fehrenbacher, L. ; Bajaj, R. ; Bathini, V. ; Fanta, P. ; Berlin, J. ; McRee, A. J. ; Maguire, R. ; Wilhelm, F. ; Maniar, M. ; Jimeno, A. ; Gomes, C. L. ; Messersmith, Wells A. / 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. In: Annals of Oncology. 2015 ; Vol. 26, No. 9. pp. 1923-1929.
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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-na{\"i}ve metastatic pancreatic adenocarcinoma. Materials and methods: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m2 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 = "Pancreatic cancer, Phase II/III, PI3K inhibitor, PLK1 inhibitor, Ras mimetic, Rigosertib",
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TY - JOUR

T1 - 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

AU - O'Neil, B. H.

AU - Scott, A. J.

AU - Ma, Wen Wee

AU - Cohen, S. J.

AU - Aisner, D. L.

AU - Menter, A. R.

AU - Tejani, M. A.

AU - Cho, J. K.

AU - Granfortuna, J.

AU - Coveler, L.

AU - Olowokure, O. O.

AU - Baranda, J. C.

AU - Cusnir, M.

AU - Phillip, P.

AU - Boles, J.

AU - Nazemzadeh, R.

AU - Rarick, M.

AU - Cohen, D. J.

AU - Radford, J.

AU - Fehrenbacher, L.

AU - Bajaj, R.

AU - Bathini, V.

AU - Fanta, P.

AU - Berlin, J.

AU - McRee, A. J.

AU - Maguire, R.

AU - Wilhelm, F.

AU - Maniar, M.

AU - Jimeno, A.

AU - Gomes, C. L.

AU - Messersmith, Wells A.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m2 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.

AB - 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/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m2 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.

KW - Pancreatic cancer

KW - Phase II/III

KW - PI3K inhibitor

KW - PLK1 inhibitor

KW - Ras mimetic

KW - Rigosertib

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