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

Lydia Usha, Michael W. Sill, Kathleen M. Darcy, Doris M. Benbrook, Jean A. Hurteau, David P. Michelin, Robert S. Mannel, Parviz Hanjani, Koenraad De Geest, Andrew K. Godwin

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)455-461
Number of pages7
JournalGynecologic Oncology
Volume121
Issue number3
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

Fingerprint

Protein Kinase C beta
Protein Kinase C
Disease-Free Survival
Neoplasms
Biomarkers
Mutation
Gene Dosage
Protein C Inhibitor
p53 Genes
Protein Kinase Inhibitors
Platinum
Vascular Endothelial Growth Factor A
Genes
Oral Administration
Disease Progression
Carcinoma
Safety
Polymerase Chain Reaction
Survival
enzastaurin

Keywords

  • AKT2
  • Enzastaurin
  • Ovarian cancer
  • PIK3CA
  • PKCβ
  • PTEN

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

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. / Usha, Lydia; Sill, Michael W.; Darcy, Kathleen M.; Benbrook, Doris M.; Hurteau, Jean A.; Michelin, David P.; Mannel, Robert S.; Hanjani, Parviz; De Geest, Koenraad; Godwin, Andrew K.

In: Gynecologic Oncology, Vol. 121, No. 3, 01.06.2011, p. 455-461.

Research output: Contribution to journalArticle

Usha, Lydia ; Sill, Michael W. ; Darcy, Kathleen M. ; Benbrook, Doris M. ; Hurteau, Jean A. ; Michelin, David P. ; Mannel, Robert S. ; Hanjani, Parviz ; De Geest, Koenraad ; Godwin, Andrew K. / 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. In: Gynecologic Oncology. 2011 ; Vol. 121, No. 3. pp. 455-461.
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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.",
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AU - Sill, Michael W.

AU - Darcy, Kathleen M.

AU - Benbrook, Doris M.

AU - Hurteau, Jean A.

AU - Michelin, David P.

AU - Mannel, Robert S.

AU - Hanjani, Parviz

AU - De Geest, Koenraad

AU - Godwin, Andrew K.

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AB - 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.

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