Official Title: “Randomized Phase II Trail Comparing Gefitinib Plus Simvastatin and Gefitinib Alone in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC)”

The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutations within the ATP binding site confers increased susceptibility to gefitinib, a potent tyrosine kinase inhibitor of EGFR. Agents that can inhibit EGFR function through different mechanisms may enhance gefitinib activity in patients lacking these mutations. Mevalonate metabolites play significant roles in the function of the EGFR; therefore, mevalonate pathway inhibitors may potentiate EGFR-targeted therapies. Targeting HMG-CoA reductase, the rate-limiting enzyme of mevalonate pathway, using lovastatin induces a potent apoptosis in a variety of tumor types. In an in vitro study, combining gefitinib and lovastatin treatment showed synergistic cytotoxic activity through enhanced inhibition of AKT activation by EGF in NSCLC and head & neck cancer cell lines. Therefore, we would like to compare the combination effect of gefitinib and simvastatin, the specific and protein inhibitor of HMG-CoA reductase, with gefitinib alone in previously treated patients with NSCLC.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Dose Comparison, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: February 2009

Randomization

1. Sex (female vs. male)

2. ECOG PS (0/1 vs. 2/3)

3. Number of prior regimen (one vs. two).

Gefitinib (250 mg per day) + Simvastatin (40 mg per day) PO or Gefitinib (250 mg per day) alone

until progression or unacceptable toxicity

Intervention(s) in this Clinical Trial

• Drug: Gefitinib+simvastatin
  • Gefitinib 250mg/QD po daily every 3 weeks plus Simvastatin 40mg/QD po daily every 3 weeks
• Drug: gefitinib only
  • gefitinib 250mg/QD po daily every 3 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Iressa + simvastatin
• Active Comparator: 2
  • Iressa only

Primary Measures

• Tumor response rate
  • Time Frame: the ratio between the number of responders and number of patients assessable for tumor response
    Safety Issue?: No
• Time to progression
  • Time Frame: From randomization date to disease progresssion or death date
    Safety Issue?: No

Secondary Measures

• Overall survival
  • Time Frame: the first day of treatment to death
    Safety Issue?: No
• Toxicity
  • Time Frame: the first day of treatment to 30 days after the last dose
    Safety Issue?: Yes
• Pharmacogenetic and biomarker study
  • Time Frame: before the first treatment date, each response evaluation until disease progression
    Safety Issue?: No

Inclusion Criteria:

• 1. Histologic or cytologic diagnosis of NSCLC
• 2. Stage IV or selected stage IIIB (with positive pleural effusion or multiple ipsilateral lung nodules) according to the American Joint Committee on Cancer (AJCC).
• 3. Previously treated with at least one platinum-based chemotherapy.
• 4. Before study entry, a minimum of 21 days must have elapsed since any prior chemotherapy.
• 5. Prior radiation therapy is allowed as long as the irradiated area is not the only source of measurable disease.
• 6. No other forms of cancer therapy, such as radiation, immunotherapy for at least 2 weeks before the enrollment in study.
• 7. Performance status of 0-3 on the ECOG criteria.
• 8. At least one unidimensional measurable lesion meeting Response Evaluation Criteria in Solid Tumors (RECIST. 2000).- Estimated life expectancy of at least 8 weeks.
• 9. Patient compliance that allow adequate follow-up.
• 10. Adequate hematologic (ANC count ≥ 1,000/uL, platelet count ≥ 150,000/mm3), hepatic (bilirubin level≤1.5 mg/dL, AST/ALT ≤ 80 IU/L), and renal (creatinine concentration ≤ 1.5 mg/dL) function.
• 11. Informed consent from patient or patient's relative.
• 12. Males or females at least 18 years of age.
• 13. If female: childbearing potential either terminated by surgery, radiation, or menopause, or attenuated by use of an approved contraceptive method (intrauterine device [IUD], birth control pills, or barrier device) during and for 3 months after trial. If male, use of an approved contraceptive method during the study and 3 months afterwards. Females with childbearing potential must have a urine negative hCG test within 7 days prior to the study enrollment.
• 14. No concomitant prescriptions including cyclosporin A, valproic acid, phenobarbital, phenytoin, ketoconazole.
• 15. Patients with brain metastasis are allowed unless there were clinically significant neurological symptoms or signs

Exclusion Criteria:

• 1. Presence of small-cell lung cancer alone or with NSCLC- Unresolved chronic toxic effects from previous anticancer therapy
• 2. Known severe hypersensitivity to gefitinib or any of the tablet excipients
• 3. Inability to swallow tablets
• 4. Other coexisting malignant disease (apart from basal-cell carcinoma)
• 5. More than three previous chemotherapy regimens for NSCLC
• 6. Previous treatment with an experimental agent of which the main mechanism of action is inhibition of epidermal growth factor receptor or its associated tyrosine kinase
• 7. Concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St John's wort; severe or uncontrolled systemic disease; clinically active interstitial lung disease (except uncomplicated lymphangitic carcinomatosis) pregnancy; and breastfeeding.
• 8. MI within preceding 6 months or symptomatic heart disease, including unstable angina, congestive heart failure or uncontrolled arrhythmia
• 9. Serious concomitant infection including post obstructive pneumonia
• 10. Major surgery other than biopsy within the past two weeks.
• 11. Pregnant or breast-feeding.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Cancer Center, Korea

Overall Clinical Trial Officials and Contacts

Ji-Youn Han, M.D.,Ph.D. Principal Investigator National Cancer Center, Korea  

Overall Contact: Ji-Youn Han, M.D.,Ph.D. +82-31-920-1154 jymama@ncc.re.kr

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00452244

Study ID Number: NCCCTS-06-177

ClinicalTrials.gov Identifier: NCT00452244

Health Authority: South Korea: Korea Food and Drug Administration (KFDA)