title: A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies.
abstract: OBJECTIVE
  Protein kinase C (PKC) activation contributes to proliferation and angiogenesis in epithelial ovarian or primary peritoneal carcinoma (EOC/PPC). A multi-institutional phase II trial was conducted to evaluate the efficacy and safety of PKCβ inhibitor enzastaurin in persistent or recurrent EOC/PPC and to explore potential prognostic and predictive biomarkers.
  
  
  METHODS
  Eligible women with measurable platinum-sensitive and resistant EOC/PPC were treated with continuous administration of oral enzastaurin until disease progression or unacceptable toxicity. A two-stage sequential design was used to evaluate progression-free survival (PFS) ≥6-months, tumor response, and toxicity. Translational studies included sequencing of the TP53, PTEN, PIK3CA and PKCβII genes for somatic mutations, quantitative PCR assays for AKT2 and PTEN copy number alterations, and measurement of circulating VEGF-A plasma levels.
  
  
  RESULTS
  Among 27 eligible and evaluable patients, 3 women with PFS≥6-months (11%) and 2 women with partial responses (7%) were observed. One of them achieved a durable response and remains on the study. No grade 4 adverse events were observed. Most common grade 3 adverse events were constitutional (4) and gastrointestinal (3). Mutations in the TP53 gene and abnormal copy number in the PTEN gene were common (56% and 48% of cases, respectively).
  
  
  CONCLUSIONS
  Enzastaurin was tolerable but had insufficient activity to proceed with the second stage of accrual. However, 1 patient has been progression-free for 44 months. No association between a biomarker and response to enzastaurin has been found. Exploratory analysis suggested an association between survival and PTEN copy number losses.
authors.affiliation: Department of Medicine, Rush University Medical Center, 1725 West Harrison Street, Chicago, IL 60612, USA. lydia_usha@rush.edu
authors.forename: Lydia
authors.initials: L
authors.lastname: Usha
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Darcy
authors.forename: Doris M
authors.initials: DM
authors.lastname: Benbrook
authors.forename: Jean A
authors.initials: JA
authors.lastname: Hurteau
authors.forename: David P
authors.initials: DP
authors.lastname: Michelin
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mannel
authors.forename: Parviz
authors.initials: P
authors.lastname: Hanjani
authors.forename: Koen
authors.initials: K
authors.lastname: De Geest
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D000077216:Carcinoma, Ovarian Epithelial; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D016158:Genes, p53; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C504878:enzastaurin