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.
RCT Entities:
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: Robert L Keith; Patrick J Blatchford; John Kittelson; John D Minna; Karen Kelly; Pierre P Massion; Wilbur A Franklin; Jenny Mao; David O Wilson; Daniel T Merrick; Fred R Hirsch; Timothy C Kennedy; Paul A Bunn; Mark W Geraci; York E Miller Journal: Cancer Prev Res (Phila) Date: 2011-06
Authors: Jenny T Mao; Michael D Roth; Michael C Fishbein; Denise R Aberle; Zuo-Feng Zhang; Jian Yu Rao; Donald P Tashkin; Lee Goodglick; E Carmack Holmes; Robert B Cameron; Steven M Dubinett; Robert Elashoff; Eva Szabo; David Elashoff Journal: Cancer Prev Res (Phila) Date: 2011-07
Authors: C H Hennekens; J E Buring; J E Manson; M Stampfer; B Rosner; N R Cook; C Belanger; F LaMotte; J M Gaziano; P M Ridker; W Willett; R Peto Journal: N Engl J Med Date: 1996-05-02 Impact factor: 91.245
Authors: G S Omenn; G E Goodman; M D Thornquist; J Balmes; M R Cullen; A Glass; J P Keogh; F L Meyskens; B Valanis; J H Williams; S Barnhart; S Hammar Journal: N Engl J Med Date: 1996-05-02 Impact factor: 91.245
Authors: Yun Oh; Roy S Herbst; Howard Burris; Ann Cleverly; Luna Musib; Michael Lahn; Gerold Bepler Journal: J Clin Oncol Date: 2008-03-01 Impact factor: 44.544
Authors: Nagi B Kumar; Gwendolyn P Quinn; Mark G Alexandrow; Jhanelle Gray; Michael Schell; Steve Sutton; Eric B Haura Journal: J Clin Trials Date: 2014-09