Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers.

Abstract

BACKGROUND:

Chemoprevention for lung cancer with nutraceutical or anti-inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. The authors of this report evaluated enzastaurin, a selective protein kinase C-β (PKC-β) inhibitor with antiproliferative and proapoptotic properties, in former smokers.

METHODS:

The primary objective of this study was to compare the average fraction of Ki-67-stained cells (the Ki-67 labeling index [LI]) in bronchial biopsy specimens that were collected before and after treatment. Participants were randomized (2:1) to receive either 6 months of daily oral enzastaurin (500 mg) or placebo. Stratification was based on morphology, history of lung cancer, and airway obstruction.

RESULTS:

In pretrial investigations, the rationale for PKC-β inhibition and pathway interrogation was established in premalignant lesions and early stage lung cancer. In an intent-to-treat analysis, of 40 randomized participants, there was no significant difference in the pretreatment/post-treatment change in the Ki-67 LI between the enzastaurin group and the placebo group (P = .53). Six participants discontinued enzastaurin, including 4 participants who had adverse events, including abdominal distension, deep vein thrombosis, hyponatremia, and rash, and 2 participants who decided to discontinue. One participant in the placebo group was discontinued on the study because of noncompliance. Two participants had ≥1 serious adverse event (bradycardia, deep vein thrombosis, and hypotension).

CONCLUSIONS:

To the authors' knowledge, this represents the first chemoprevention trial with a non-US Food and Drug Administration-approved, oral, small-molecule-targeted agent. Although the primary endpoint was not met, enzastaurin was tolerable for 6 months by 75% of participants, and there was a suggestion of response in a subset analysis that was restricted to those who had metaplastic or dysplastic lesions.

• Authors: Jhanelle E Gray, Soner Altiok, Mark G Alexandrow, Frank W Walsh, Jian Chen, Michael J Schell, Datchen Fritz Tai, Gerold Bepler
• Journal: Cancer (Cancer) Vol. 119 Issue 5 Pg. 1023-32 (Mar 01 2013) ISSN: 1097-0142 [Electronic] United States
• PMID: 23065656 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Cancer Society.

Chemical References

• Indoles
• Protein Kinase Inhibitors
• Protein Kinase C
• Protein Kinase C beta
• enzastaurin

Topics

• Aged
• Female
• Humans
• Indoles (adverse effects, pharmacology)
• Lung Neoplasms (prevention & control)
• Male
• Middle Aged
• Precancerous Conditions (drug therapy)
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase C beta
• Protein Kinase Inhibitors (pharmacology)
• Risk
• Smoking (adverse effects)