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 |
| |
Authors: | Usha Lydia Sill Michael W Darcy Kathleen M Benbrook Doris M Hurteau Jean A Michelin David P Mannel Robert S Hanjani Parviz De Geest Koen Godwin Andrew K |
| |
Institution: | a Department of Medicine, Rush University, Chicago, IL 60612, USAb Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USAc Department of Biostatistics, State University of New York at Buffalo, Buffalo, NY 14201, USAd Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USAe University of Chicago Pritzker School of Medicine, Division of Gynecologic Oncology, North Shore University Health System, Evanston Hospital, Evanston, IL 60201, USAf Munson Medical Center, Gynecologic Oncologist, Traverse City MI 49684, USAg Abington Memorial Hospital, Rosenfeld Cancer Center, Abington, PA 19001, USAh Department of Gynecologic Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242-1080, USAi Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA |
| |
Abstract: | ObjectivesProtein 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.MethodsEligible 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.ResultsAmong 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).ConclusionsEnzastaurin 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. |
| |
Keywords: | Enzastaurin Ovarian cancer PKCβ PTEN PIK3CA AKT2 |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|