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

Abstract

BACKGROUND Chemoprevention for lung cancer with neutraceuticals or anti-inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. Here, we evaluated enzastaurin, a selective PKC-β inhibitor with antiproliferative and proapoptotic properties in former smokers. METHODS The primary objective was to compare the average fraction of Ki-67 stained cells (labeling index [LI]) in bronchial biopsies collected before and after treatment. Subjects were randomized (2:1) to 6 months of daily oral enzastaurin (500mg) or placebo. Stratification was based on morphology, history of lung cancer, and airway obstruction. RESULTS In pretrial investigations, we established the rationale for PKC-β inhibition and pathway interrogation in premalignant lesions and early stage lung cancer. In the intent-to-treat analysis, of 40 subjects randomized, there was no significant difference in the pre/post-treatment change of the Ki-67 LI between the enzastaurin and placebo groups (p = 0.53). Six subjects discontinued enzastaurin (n=4, AEs: abdominal distension, DVT, hyponatremia, and rash; n=2, subject decision) and one placebo (noncompliance). Two subjects had ≥1 serious AEs (bradycardia, DVT, and hypotension). CONCLUSIONS This represents the first chemoprevention trial with a non-FDA-approved, oral, small-molecule targeted agent. Although the primary endpoint was not met, enzastaurin was found to be tolerable for 6 months by 75% of subjects with a suggestion of response in a subset analysis restricted to metaplastic or dysplastic lesions.

Chemoprevention Trial Feasibility Using Botanicals in Exceptionally High Risk Populations for Lung Cancer

“…These challenges are significantly associated with protocol and patient-related factors, including the behavioral dynamics of the research team, institutional infrastructure, community and participating subjects [14]. Although other research teams [8,16] have examined feasibility of strategies used to recruit former smokers in chemoprevention trials, these strategies remain costly, not targeted to specific populations nor contemporary. Once the target population, the source of subjects and agent to be evaluated have been identified, it is critical for research teams to carefully examine the potential challenges and facilitators unique to the target population, study agent and disease site as a first step of the design phase of a lung cancer chemoprevention trial.…”

“…However, these strategies have limitations in that they may be unsuccessful in recruiting of economically disadvantaged as well as low literacy individuals, who are underrepresented among individuals with health insurance or with ready access to social media sites. Our group was able to access a database that was successfully utilized to recruit subjects for a secondary chemoprevention trial from this population, similar to what would be proposed based on this study [8] at exceptional risk that had prior familiarity with the environment and research teams. However, we noted significant attrition of subjects who were no longer at their mailing address.…”

“…Forty (40) subjects from this database have previously been recruited to other chemoprevention trials successfully [8]. We included subjects from this database who met the following inclusion criteria: age 50 years or over, a 30 pack-year history of smoking but had quit smoking, metaplasia or dysplasia on at least 1 bronchoscopy specimen.…”

“…Cox-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) and enzastaurin (LY317615) have been evaluated for the chemoprevention of lung cancer in former or current smokers. However, poor effectiveness or cardiovascular and other toxicities have limited their clinical adoption [8,9]. Other chemopreventive agents evaluated include beta-carotene, alpha-tocopherol, retinol, retinyl palmitate, N-acetylcysteine, or isotretinoin [10-13].…”

Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status

“…In pre-clinical models, enzastaurin displayed activity against cancer cells from different entities including carcinomas, glioblastoma, melanoma, and different haematological malignancies as well as anti-angiogenic effects [2][3][4][5][6][7][8][9][10][11][12][13]. The substance has been investigated for its effects against various cancer types in clinical trials [4,[13][14][15][16][17][18][19][20][21][22].…”