Gefitinib With or Without Simvastatin in Non-Small Cell Lung Cancer (NSCLC)

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, the investigators 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 Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: simvastatin; Drug: gefitinib only

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of
      • National Cancer Center, Korea

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: study arm; Iressa (gefitinib) + simvastatin	Drug: simvastatin; Simvastatin 40mg/QD po daily every 3 weeks; Other Names: IRESSA; simvarstar; Drug: gefitinib only; gefitinib 250mg/QD po daily every 3 weeks; Other Names: IRESSA
Active Comparator: control arm; Iressa (gefitinib) only	Drug: gefitinib only; gefitinib 250mg/QD po daily every 3 weeks; Other Names: IRESSA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response rate	from C1D1 until confirmed disease progression	every 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	the first day of treatment to death	every 12 weeks
Toxicity	From C1D1 to 1 months after the last dose adminitration	every 4 weeks
Pharmacogenetic and biomarker profile analysis	From screening visit until confirmed disease progression	every 8 weeks
Time to progression	From randomization date to disease progresssion or death date	every 8 weeks

Collaborators and Investigators

• Sponsor: National Cancer Center, Korea
• Investigators: Principal Investigator: Ji-Youn Han, M.D.,Ph.D., National Cancer Center, Korea

Publications and helpful links

General Publications

• Han JY, Kim JY, Lee SH, Yoo NJ, Choi BG. Association between plasma hepatocyte growth factor and gefitinib resistance in patients with advanced non-small cell lung cancer. Lung Cancer. 2011 Nov;74(2):293-9. doi: 10.1016/j.lungcan.2011.02.021. Epub 2011 Mar 26.
• Han JY, Lee SH, Yoo NJ, Hyung LS, Moon YJ, Yun T, Kim HT, Lee JS. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011 Mar 15;17(6):1553-60. doi: 10.1158/1078-0432.CCR-10-2525.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: March 26, 2007
• First Submitted That Met QC Criteria: March 26, 2007
• First Posted (Estimate): March 27, 2007

Study Record Updates

• Last Update Posted (Actual): August 25, 2017
• Last Update Submitted That Met QC Criteria: August 24, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: NSCLC; Simvastatin; Gefitinib; Advanced NSCLC
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Protein Kinase Inhibitors; Gefitinib; Simvastatin
• Other Study ID Numbers: NCCCTS-06-177