Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Enzastaurin in Preventing Non-Small Cell Lung Cancer in Former Smokers

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Biomarker/Laboratory analysis, Prevention Active 45 and over NCI, Pharmaceutical / Industry MCC-14787 MCC-104545, LILLY-H6Q-MC-S009A, U01-CA-101222, NCT00387816

Objectives

Primary

1. Compare the difference between the average Ki-67 LI (percentage of cells positively labeled with Ki-67, a marker of cellular proliferation) in all bronchial biopsy specimens of former smokers before and after treatment with enzastaurin hydrochloride vs placebo.

Secondary

1. Compare the adverse events in patients treated with these regimens.

Tertiary

1. Assess target inhibition in patients treated with these regimens.
2. Assess target inhibition of GSK3β in patients treated with these regimens.
3. Assess MCM2, cleaved caspase 3, pPKCβ, and pGSK3β by immunohistochemistry in patients treated with these regimens.
4. Measure metaplasia/dysplasia by light microscopy in samples from patients treated with these regimens.
5. Assess fractional allele loss by single nucleotide polymorphism chip arrays in samples from patients treated with these regimens.
6. Assess cytokine response profiles by western analysis for pStat3 and pErk1/2 of short-term cultures after exposure to epidermal growth factor and interleukin-6 in samples from patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• History of cigarette smoking ≥ 30 pack years



• Quit smoking ≥ 1 year prior to study entry
  • Must be willing to abstain from smoking and avoid second-hand smoke exposure



• Negative cotinine by urine dipstick



• Cytologically confirmed sputum atypia in an induced sputum specimen collected on site



• Metaplasia or dysplasia on at least one bronchoscopy specimen



• No evidence of lung cancer or carcinoma in situ by sputum cytology, helical CT scan, or bronchoscopy
  • Patients with history of stage IA or IB non-small cell lung cancer allowed provided all of the following criteria are met:
    • Completely resected ≥ 12 months ago
    • No evidence of recurrence
    • At least 1 mediastinal lymph node station negative for cancer



• No history of small cell lung cancer

Prior/Concurrent Therapy:

• No prior anticancer chemotherapy or hormonal therapy
• More than 5 years since prior radiotherapy to the chest
• More than 6 months since prior major surgery
• More than 6 months since prior cardiac surgery or percutaneous transluminal coronary angioplasty
• At least 6 months since prior chemoprevention trial
• No concurrent participation in another chemoprevention trial
• At least 14 days since prior and no concurrent enzyme-inducing antiepileptic drugs
• More than 30 days since prior and no concurrent investigational agents
• No concurrent illicit drug or ethanol abuse
• No other concurrent anticancer therapy, immunotherapy, hormonal therapy, or curative radiotherapy

Patient Characteristics:

• ECOG performance status 0-1
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 1.5 times ULN
• ALT and AST ≤ 1.5 times ULN
• Creatinine < 1.5 mg/dL
• Able to undergo bronchoscopy and helical CT scanning of the chest
• Able to swallow tablets
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known coagulopathy (INR > 1.5, PT > 37.0 sec)
• No history of malignancy within the past 5 years, except for any of the following:
  • Nonmelanoma skin cancer
  • Cervical carcinoma in situ
• No active pulmonary infection
• No sarcoidosis
• No connective tissue disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, sclerosing cholangitis, or Wegener’s granulomatosis)
• No chronic obstructive pulmonary disease, asthma, or sleep apnea requiring inhaled steroids, bronchodilators, or oxygen
• No cerebrovascular accident or transient ischemic attack within the past 6 months
• No active coronary artery disease
• No ECG abnormalities indicative of cardiac disease
• No active peptic ulcer disease
• No mental illness that would preclude study participation
• No investigator site personnel directly affiliated with study and/or their immediate families
  • Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted
• Not an employee at Eli Lilly and Company

Expected Enrollment

A total of 186 patients will be accrued for this study.

Outcomes

Difference between average Ki-67 LI (percentage of cells positively labeled with Ki-67) before and after completion of treatment

Target inhibition
Target inhibition of GSK3β
Biomarkers MCM2, cleaved caspase 3, pPKCβ, and pGSK3β as assessed by immunohistochemistry
Metaplasia or dysplasia as assessed by light microscopy
Fractional allele loss as assessed by single nucleotide polymorphism chip arrays
Cytokine response profiles as measured by western analysis

Outline

This is a randomized, placebo-controlled, double-blind study. Patients are stratified according to history of stage I non-small cell lung cancer (yes vs no), evidence of airway obstruction (FEV₁/FVC ≤ 0.7 vs > 0.7), and pretreatment bronchial biopsy histology (presence vs absence of dysplasia). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral enzastaurin hydrochloride once daily for 6 months in the absence of disease progression or unacceptable toxicity.



• Arm II: Patients receive oral placebo once daily for 6 months in the absence of disease progression or unacceptable toxicity.

In both arms, all patients undergo blood collection and bronchoscopy with brushings and biopsies after completion of treatment.

Laboratory studies are conducted on tissue and blood samples to measure biological markers, including Ki-67, PKCβ2, GSK3β, and MCM2, and to assess apoptosis, morphology, cytokine response profiles, and genetic alterations by immunohistochemistry and western analysis.

After completion of study treatment, patients are followed at 12 and 24 months.

Trial Contact Information

Trial Lead Organizations

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida

Gerold Bepler, MD, PhD, Principal investigator		Ph: 813-745-6895; 888-663-3488 Email: gerold.bepler@moffitt.org

U.S.A.
Florida
	Tampa
	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
		Clinical Trials Office - H. Lee Moffitt Cancer Center and Reseach Institute	Ph:  800-456-7121
			Email: canceranswers@moffitt.org

Registry Information
Official Title		A Phase IIB Randomized, Placebo-Controlled, Double-Blind Study of Enzastaurin HCL (LY317615) for Lung Cancer Prevention in Former Smokers
Trial Start Date		2007-10-15
Trial Completion Date		2008-10-15 (estimated)
Registered in ClinicalTrials.gov		NCT00387816
Date Submitted to PDQ		2006-09-14
Information Last Verified		2008-04-20
NCI Grant/Contract Number		CA101222, CA76292