title: 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: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.affiliation: Simon Cancer Center, Indiana University School of Medicine, Indianapolis.
authors.forename: B H
authors.initials: BH
authors.lastname: O'Neil
authors.affiliation: University of Colorado, Denver, Aurora.
authors.forename: A J
authors.initials: AJ
authors.lastname: Scott
authors.affiliation: Roswell Park Cancer Institute, Buffalo.
authors.forename: W W
authors.initials: WW
authors.lastname: Ma
authors.affiliation: Fox Chase Cancer Center, Philadelphia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Cohen
authors.affiliation: University of Colorado, Denver, Aurora.
authors.forename: D L
authors.initials: DL
authors.lastname: Aisner
authors.affiliation: Kaiser Permanente, Lone Tree.
authors.forename: A R
authors.initials: AR
authors.lastname: Menter
authors.affiliation: University of Rochester Medical Center, Rochester.
authors.forename: M A
authors.initials: MA
authors.lastname: Tejani
authors.affiliation: Oncare Hawaii, Honolulu.
authors.forename: J K
authors.initials: JK
authors.lastname: Cho
authors.affiliation: Cone Health Cancer Center, Greensboro.
authors.forename: J
authors.initials: J
authors.lastname: Granfortuna
authors.affiliation: University of Washington, Seattle.
authors.forename: L
authors.initials: L
authors.lastname: Coveler
authors.affiliation: University of Cincinnati Cancer Institute, Cincinnati.
authors.forename: O O
authors.initials: OO
authors.lastname: Olowokure
authors.affiliation: University of Kansas Medical Center, Westwood.
authors.forename: J C
authors.initials: JC
authors.lastname: Baranda
authors.affiliation: Mount Sinai Medical Center, Miami Beach.
authors.forename: M
authors.initials: M
authors.lastname: Cusnir
authors.affiliation: Karmanos Cancer Institute, Detroit.
authors.forename: P
authors.initials: P
authors.lastname: Phillip
authors.affiliation: Rex Cancer Center UNC Healthcare, Raleigh.
authors.forename: J
authors.initials: J
authors.lastname: Boles
authors.affiliation: Carolinas Health Care, Charlotte.
authors.forename: R
authors.initials: R
authors.lastname: Nazemzadeh
authors.affiliation: Kaiser Permanante Northwest, Portland.
authors.forename: M
authors.initials: M
authors.lastname: Rarick
authors.affiliation: NYU Clinical Cancer Center, New York.
authors.forename: D J
authors.initials: DJ
authors.lastname: Cohen
authors.affiliation: Hendersonville Hematology and Oncology at Pardee, Hendersonville.
authors.forename: J
authors.initials: J
authors.lastname: Radford
authors.affiliation: Kaiser Permanante Medical Center, Vallejo.
authors.forename: L
authors.initials: L
authors.lastname: Fehrenbacher
authors.affiliation: McLeod Regional Medical Center, Florence.
authors.forename: R
authors.initials: R
authors.lastname: Bajaj
authors.affiliation: University of Massachusetts Memorial, Worcester.
authors.forename: V
authors.initials: V
authors.lastname: Bathini
authors.affiliation: UCSD Moores Cancer Center, La Jolla.
authors.forename: P
authors.initials: P
authors.lastname: Fanta
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville.
authors.forename: J
authors.initials: J
authors.lastname: Berlin
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill.
authors.forename: A J
authors.initials: AJ
authors.lastname: McRee
authors.affiliation: Onconova Therapeutics Inc., Newtown.
authors.forename: R
authors.initials: R
authors.lastname: Maguire
authors.affiliation: Onconova Therapeutics Inc., Newtown.
authors.forename: F
authors.initials: F
authors.lastname: Wilhelm
authors.affiliation: Onconova Therapeutics Inc., Newtown.
authors.forename: M
authors.initials: M
authors.lastname: Maniar
authors.affiliation: University of Colorado, Denver, Aurora.
authors.forename: A
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Oncology Consortia of Criterium Inc., Saratoga Springs, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Gomes
authors.affiliation: University of Colorado, Denver, Aurora. Electronic address: wells.messersmith@ucdenver.edu.
authors.forename: W A
authors.initials: WA
authors.lastname: Messersmith
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D003841:Deoxycytidine; D005998:Glycine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D013450:Sulfones; D016159:Tumor Suppressor Protein p53; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1; C117307:KRAS protein, human; C495901:TP53 protein, human; C507134:ON 01910; C484760:PIK3CA protein, human
keywords: PI3K inhibitor; PLK1 inhibitor; Ras mimetic; pancreatic cancer; phase II/III; rigosertib