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

Objectives: 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.

Trial registration: ClinicalTrials.gov NCT00407758.

Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors declare that there are no conflicts of interest.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

(A) Kaplan-Meier estimate of progression-free survival (solid line) and overall survival (dashed line) for women treated with enzastaurin, and (B) the PFS1for those treated with enzastaurin (solid line) compared with non-randomized GOG historical controls (dashed lines).

Figure 1

(A) Kaplan-Meier estimate of progression-free survival (solid line) and overall survival (dashed line) for women treated with enzastaurin, and (B) the PFS1for those treated with enzastaurin (solid line) compared with non-randomized GOG historical controls (dashed lines).

Figure 2

Overall survival of patients in the study cohort based on PTEN copy number in tumors Kaplan-Meier survival distributions for PTEN loss (solid line), PTEN stable (long dashed line) and PTEN gain (short dashed line) and log-rank (permutation test) suggest potential association between copy number alterations (CNAs) in PTEN and survival.