Metformin in Stage IV Lung Adenocarcinoma

A Phase II Trial to Examine the Effect of Metformin on Plasma IL-6 Level in Patients With Advanced Non-Small Cell Lung Cancer

The purpose of this study is to determine whether metformin is effective in lowering plasma IL-6 level and improving the treatment response in patients with non-small cell lung cancer

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: METFORMIN

Detailed Description

Interleukin-6 (IL-6) plays an important role in the pathogenesis of lung cancer. Several clinical studies show metformin could decrease IL-6 level in addition to the glucose-lowering effect. Preclinical data also reveal metformin could decrease the IL-6 production in lung cancer cells and enhance cytotoxicity of chemotherapy in animal model. Based on these findings, the purpose of this study is to determine whether metformin is effective in lowering plasma IL-6 level and improving the treatment response in patients with non-small cell lung cancer clinically. Patients with stage IV lung adenocarcinoma will be enrolled in this study and receive standard treatments for lung cancer, either chemotherapy combining cisplatin and pemetrexed or targeted therapy (Gefitinib). For patients with plasma IL-6 more than 2.0 pg/ml after 2 cycles of standard treatment, metformin will be given and titrated to 1500mg/day gradually. Plasma IL-6 level will be checked after use of metformin for 12 weeks. Tumor response to the standard treatment plus metformin will be evaluated and side effects of metformin will also be monitored.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Tainan, Taiwan, 704
    • National Cheng-Kung Uni. Hosp.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed lung adenocarcinoma.
2. Stage IV disease as defined by AJCC 7th edition staging.
3. At least one measurable lesion (as defined by RECIST v1.1).
4. No prior radiotherapy, chemotherapy, surgery, target therapy, or immunotherapy for NSCLC. (Except the surgery for biopsy or port-A implantation, palliative localized radiotherapy for bone metastasis).
5. Age ≤ 80 years old and ≥ 20 years old.
6. ECOG performance status of 0-2.

7. Adequate organ function, including followings

   Bone marrow:

   Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; WBC ≥ 3.0 x 10^9/L Platelet count ≥ 100 x 10^9/L Hemoglobin ≥ 9g/dL

   Hepatic:

   Total bilirubin level ≤ 1.0 x UNL AST and ALT ≤ 3.0 x UNL;

   Renal:

   Creatinine level ≤ 1.5 mg/dL in men, ≤1.4 mg/dL in women; or Estimated CCr ≥ 60 mL/min. (CCr is estimated by Cockcroft-Gault formula, as appendix II)(CCr is estimated by Cockcroft-Gault formula)

8. Estimated life expectancy of at least 6 months.
9. Written (signed) Informed Consent.

Exclusion Criteria:

1. With other primary malignancies, except those remain disease-free for 3 or more years after curative treatment, basal cell cancer of the skin or in situ cervical cancer.
2. Use of other anti-cancer therapy, including chemotherapy, target therapy, immunotherapy, radiotherapy, and hormone therapy.
3. Prior participation in any investigational drug study within 28 days.
4. Use of anti-IL-6 or IL-6-lowering agents.
5. Use of metformin in the past 6 months.
6. Poor controlled diabetes (HbA1c ≥ 8.0%).
7. Known hypersensitivity or intolerance to metformin.
8. Congestive heart failure with NYHA functional class II~IV.
9. History of lactic acidosis.
10. Significant concurrent medical diseases, such as unstable angina, acute or recent myocardial infarction (< 6 months before enrollment), COPD with frequent exacerbation, uncontrolled hypertension, or recent CVA (< 6 months before enrollment).
11. Active uncontrolled infections or HIV infection.
12. Psychiatric disorders that would compromise the patient's compliance or decision.
13. Current or planned pregnancy, or breast feeding in women.
14. Poor compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: METFORMIN; For patients with stage IV lung adenocarcinoma and IL-6 level higher than 2.0 pg/ml after 2 cycles of standard treatment, metformin 500mg tid orally will be given.

Drug: METFORMIN; Participants enrolled in this study will be treated with either chemotherapy (Cisplatin 75mg/m2 plus Pemetrexed 500mg/m2 on D1) for 4 cycles or targeted therapy (Gefitinib 250mg/d) till disease progression according to physicians' decision. For participants with plasma IL-6 > 2.0 pg/mL after 2 cycles of chemotherapy or targeted therapy, Metformin 500mg orally qd will be given on Day 1 of cycle 3. If patient could tolerate it well, metformin will be titrated to 500mg bid in the following week (Cycle 3 D8) and 500mg tid in the 3rd week (Cycle 3 D15). For patients receiving chemotherapy, metformin will be used for total 12 weeks and plasma IL-6 level will be checked at the end of metformin treatment. For patients receiving targeted therapy, metformin will be used till disease progression and plasma IL-6 level will be measured after use of metformin for 12 weeks.; Other Names: GLUCOPHAGE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The change of plasma IL-6 level after the treatment with metformin	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The objective response rate (RR)		2 YEARS
The progression free survival		2 years
The overall survival		2-years
Number of participants with adverse events	All adverse events (AEs) occurring after the patient receiving the first dose of study drug will be monitored and recorded. Periodic measurement of vital signs, regular laboratory evaluation for hematology and blood chemistry will be arranged and these will be graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grades.	2-years
Changes of quality of life	The quality of life will be evaluated by the EQ-5D-3L questionnaire which will be completed at baseline, during the therapy, and post-therapy period	2-years

Collaborators and Investigators

• Sponsor: National Cheng-Kung University Hospital
• Investigators: Principal Investigator: YUMIN YEH, MD, National Cheng-Kung Uni. Hosp.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: November 17, 2013
• First Submitted That Met QC Criteria: November 24, 2013
• First Posted (Estimate): November 28, 2013

Study Record Updates

• Last Update Posted (Estimate): September 30, 2016
• Last Update Submitted That Met QC Criteria: September 29, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Metformin; Non-small cell lung cancer; IL-6; Lung adenocarcinoma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: B-BR-102-039

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO