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A Phase II, Randomized, Placebo Controlled Study to Evaluate the Efficacy of the Combination of Gefitinib and Metformin in Patients With Locally Advanced and Metastatic Non-Small-Cell-Lung-Cancer

Phase 2
18 Years
75 Years
Open (Enrolling)
NSCLC, EGFR Gene Amplification, Advanced Cancer, Stage IIIB NSCLC, Stage IV NSCLC

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Trial Information

A Phase II, Randomized, Placebo Controlled Study to Evaluate the Efficacy of the Combination of Gefitinib and Metformin in Patients With Locally Advanced and Metastatic Non-Small-Cell-Lung-Cancer

Primary Objectives: To determine the 1 year progression-free survival (PFS) of the
combination of metformin and gefitinib in patients who harbors EGFR-mutant with previously
untreated advanced or metastatic pulmonary adenocarcinoma.

Secondary Objectives:

A. To evaluate the response to therapy and overall survival of the combination of metformin
with gefitinib in patients who harbors EGFR-mutant with previously untreated advanced or
metastatic pulmonary adenocarcinoma.

B. To acquire preliminary data regarding the effects of metformin on interleukin-6 (IL-6)
levels in tumor and serum.

Treatment will be administered on an outpatient basis. Metformin starting at a dose of 500
mg twice a day, orally with meals. After one week, increase the dose of metformin to 1000 mg
as the first dose of the day and 500 mg as the second dose. After another week, increase to
1000 mg of metformin two times a day. Metformin treatment will be initiated one week before
beginning gefitinib, if possible, but gefitinib administration will not be delayed for
metformin loading.

Gefitinib will be administered 250mg QD continuously. Metformin will be administered
continuously, beginning one week before beginning gefitinib, if possible, but tyrosine
kinase inhibitors (TKI) will not be delayed for metformin loading.

Maintenance Therapy Patients responding to this therapy will be maintained with metformin
(1000 mg twice daily) and gefitinib.

Duration of Therapy

In the absence of treatment delays due to adverse events, treatment may continue until one
of the following criteria applies:

1. Disease progression,

2. Intercurrent illness that prevents further administration of treatment,

3. Unacceptable adverse events(s),

4. Patient decides to withdraw from the study, or

5. General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator.

Inclusion Criteria:

- Patients must have Histologically or cytologically confirmed non small cell carcinoma
of the lung who harbors EGFR-mutation and are previously untreated

- Patient must have measurable stage IV disease (includes M1a, M1b stages or recurrent
disease) (according to the 7th edition of the tumor node metastasis (TNM)
classification system). However, patients with T4NX disease (stage III B) with
nodule(s) in ipsilateral lung lobe are not eligible, because such patients were not
included in historical controls.

- Patients be age >18 years and < 75 years.

- Patients must have a Life Expectancy of greater than 12 weeks.

- Patients must have an electrocorticography (ECOG) performance status 0 or 1
(Karnofsky > 70%).

- Patients must have normal organ and marrow function as defined below, within one week
prior to randomization:

absolute neutrophil count >1,500/mL platelets > 100,000/mL total bilirubin: within normal
institutional limits AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal
creatinine ≤ 1.5 X institutional upper limit of normal urine dipstick for proteinuria of <
less than 1+. If urine dipstick is > 1+ then a 24 hour urine for protein must demonstrate
< 500 mg of protein in 24 hours to allow participation in the study.

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.

- Patients must have an international normalized ratio (INR) < 1.5 and a partial
thromboplastin time (PTT) no greater than upper limits of normal within 1 week prior
to randomization.

- Patients with a history of hypertension must be well-controlled (<150 systolic/<100
diastolic) on a stable regimen of anti-hypertensive therapy.

- Patients must have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would
limit compliance with study requirements.

- Patients receiving chronic daily treatment with aspirin (> 325 mg/day) or
nonsteroidal anti-inflammatory agents known to inhibit platelet function. Treatment
with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or
cilostazol (Pletal)is also not allowed.

- Patients receiving therapeutic anticoagulation. Prophylactic anticoagulation of
venous access devices is allowed provided Section 3.10 is met. Caution should be
taken on treating patients with low dose heparin or low molecular weight heparin for
DVT prophylaxis during treatment with bevacizumab as there may be an increased risk
of bleeding.

- Prior use of chemotherapy.

- Patients receiving immunotherapy, hormonal-therapy and or radiotherapy within 2 weeks
prior to entering the study. Note: Those who have not recovered from adverse events
due to these agents administered will be considered ineligible.

- Patients receiving any other investigational agents.

- Patients with uncontrolled brain metastasis. Note: Patients with brain metastases
must have stable neurologic status following local therapy (surgery or radiation) for
at least 2 weeks, and must be without neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events.

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to metformin and paclitaxel or other agents used in
the study are excluded.

- Women that are pregnant or breastfeeding Note: Pregnant women are excluded from this
study because the agents used in this study may be teratogenic to a fetus. Because
there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with paclitaxel, breastfeeding women are also
excluded from this study.

- Patients that are HIV-positive on combination antiretroviral therapy due to the
potential for lethal infections when treated with marrow-suppressive therapy.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

One year progression-free survival (PFS) of the patients.

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Yong He, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Daping Hospital, Third Military Medical University


China: Third Military Medical University

Study ID:




Start Date:

May 2013

Completion Date:

May 2017

Related Keywords:

  • EGFR Gene Amplification
  • Advanced Cancer
  • Stage IIIB NSCLC
  • Stage IV NSCLC
  • TKIs
  • Metformin
  • PFS
  • overall survival
  • IL-6
  • Carcinoma, Non-Small-Cell Lung
  • Neoplasms