title: Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer.
abstract: OBJECTIVE
  Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer.
  
  
  METHODS
  Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA).
  
  
  RESULTS
  Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m(2)): 750/600 (n = 4), 750/1,200 (n = 3), 1,000/600 (n = 3), 1,000/1,200 (n = 3), and 1,000/1,800 (n = 6 + 21). One dose-limiting toxicity (death) occurred at the highest dose level (1,000/1,800) tested. Non-dose-limiting ≥grade II/III toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade III/IV neutropenia, thrombocytopenia, and fatigue were seen in two, one, and two patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer, and Hodgkin lymphoma, including gemcitabine-pretreated PDA. The pharmacokinetic profile of rigosertib was not affected by gemcitabine.
  
  
  CONCLUSIONS
  The RPTD established in this study is rigosertib 1,800 mg/m(2) and gemcitabine 1,000 mg/m(2). This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy.
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York; University of Colorado Cancer Center, Aurora, CO 80045,USA.
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.forename: Colin D
authors.initials: CD
authors.lastname: Weekes
authors.forename: Amy
authors.initials: A
authors.lastname: Whitworth
authors.forename: Chen
authors.initials: C
authors.lastname: Ren
authors.forename: Manoj
authors.initials: M
authors.lastname: Maniar
authors.forename: Francois
authors.initials: F
authors.lastname: Wilhelm
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D018797:Cell Cycle Proteins / Q000378:metabolism; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D005998:Glycine; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013450:Sulfones; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1; C507134:ON 01910