title: Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study.
abstract: OBJECTIVE
  Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCβ and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes.
  
  
  METHODS
  Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg p.o. daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m(2) i.v. Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry.
  
  
  RESULTS
  Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3-4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3β trended toward greater OS with GE treatment.
  
  
  CONCLUSIONS
  OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.
authors.affiliation: US Oncology Research, Inc., The Woodlands, TX, USA. Donald.Richards@USOncology.com
authors.forename: Donald A
authors.initials: DA
authors.lastname: Richards
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kuefler
authors.forename: Carlos
authors.initials: C
authors.lastname: Becerra
authors.forename: Lalan S
authors.initials: LS
authors.lastname: Wilfong
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gersh
authors.forename: Kristi A
authors.initials: KA
authors.lastname: Boehm
authors.forename: Feng
authors.initials: F
authors.lastname: Zhan
authors.forename: Lina
authors.initials: L
authors.lastname: Asmar
authors.forename: Scott P
authors.initials: SP
authors.lastname: Myrand
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Hozak
authors.forename: Luping
authors.initials: L
authors.lastname: Zhao
authors.forename: John F
authors.initials: JF
authors.lastname: Gill
authors.forename: Brian P
authors.initials: BP
authors.lastname: Mullaney
authors.forename: Coleman K
authors.initials: CK
authors.lastname: Obasaju
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Nicol
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011788:Quality of Life; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D003841:Deoxycytidine; C504878:enzastaurin; D000093542:Gemcitabine