Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine whether metformin hydrochloride (MET) added to chemoradiotherapy can improve
progression-free survival (PFS) in patients with locally advanced non-small cell lung cancer
(NSCLC).

SECONDARY OBJECTIVES:

I. Determine the effects of MET on overall survival (OS), time to local-regional progression
(LRP), and time to distant metastasis (DM).

II. Evaluate the effect of MET on chemoradiotherapy toxicity (Common Terminology Criteria for
Adverse Events, version 4 [CTCAE, v. 4]) within 1 year of completion of all treatment.

III. Collect biospecimens to develop biomarkers of MET activity.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 30
minutes on days 1, 8, 15, 22, 29, and 36 and undergo radiation therapy (3-dimensional
conformal radiation therapy [3D-CRT] or intensity modulated radiation therapy [IMRT]) once
daily (QD) 5 days a week for 6 weeks. Beginning 28-42 days after completion of radiation
therapy, patients receive consolidation chemotherapy comprising paclitaxel IV and carboplatin
IV on days 1 and 22. Treatment with consolidation chemotherapy repeats every 3 weeks for 2
courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive metformin hydrochloride orally (PO) twice daily (BID) or thrice
daily (TID) for 14 days. Beginning on day 15, patients undergo radiation therapy and receive
paclitaxel and carboplatin as in Arm I, and receive metformin hydrochloride BID or TID for 6
weeks. Beginning 28-42 days after completion of radiation therapy, patients receive
consolidation chemotherapy as in Arm I and metformin hydrochloride PO BID or TID for 10
weeks.

After completion of study treatment, patients are followed up at 4-6 weeks, every 3 months
for 2 years, every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of stage IIIA or
IIIB non-small cell lung cancer within 84 days of registration; eligible histologies
include adenocarcinoma, adenosquamous, large cell carcinoma, squamous carcinoma,
non-lobar and non-diffuse bronchoalveolar cell carcinoma or non-small cell lung cancer
not otherwise specified [NOS])

- Patients must have measurable disease

- Patients must have unresectable disease, be medically inoperable, or unwilling to
undergo surgical management

- Appropriate stage for protocol entry, including no distant metastases, based upon the
following minimum diagnostic workup:

- History/physical examination, including documentation of height, weight, body
surface area [BSA], and vital signs, within 30 days prior to registration

- Computed tomography (CT) with IV contrast or magnetic resonance imaging (MRI)
imaging (if CT scan with contrast is medically contraindicated) of the lung and
upper abdomen through the adrenal glands, required within 45 days prior to
registration (recommended within 30 days prior to registration

- MRI of the brain with contrast (or CT with contrast if MRI is medically
contraindicated) within 45 days prior to registration; note: the use of
intravenous contrast is required for the MRI or CT; an MRI without contrast is
only permitted if the patient has a contrast allergy

- Whole-body fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT
required within 45 days prior to registration (recommended within 30 days prior
to registration; note: patients do not need to have a separate CT of the chest
and upper abdomen with contrast if PET/CT imaging includes a high quality CT with
contrast

- Zubrod performance status 0-1

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

- Platelets >= 100,000 cells/mm^3

- Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

- Serum creatinine within normal institutional limits or creatinine clearance must be at
least 60 ml/min

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for the institution

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN for
the institution

- Alkaline phosphatase =< 2.5 x ULN for the institution

- Fasting blood glucose =< 125 mg/dL within 14 days prior to registration

- Serum albumin > 3.0 g/dl within 14 days prior to registration

- For women of childbearing potential, a serum pregnancy test within 72 hours prior to
registration

- Patients with post-obstructive pneumonia are eligible provided they no longer require
intravenous antibiotics at registration

- Patients must be at least 3 weeks from prior thoracotomy (if performed)

- If a pleural effusion is present, the following criteria must be met at registration
to exclude malignant involvement (incurable M1a disease):

- When pleural fluid is visible on both the CT scan and on a chest x-ray, a
pleuracentesis is required to confirm that the pleural fluid is cytologically
negative

- Effusions that are minimal (i.e. not visible under ultrasound guidance) and that
are too small to safely tap are eligible

- Women of childbearing potential and male participants must practice adequate
contraception throughout the study

- Patient must provide study specific informed consent prior to study entry

Exclusion Criteria:

- Patients with mixed small cell and non-small cell histologies

- Patients with distant metastasis

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity,
or cervix are all permissible)

- Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
different cancer is allowable

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields

- Patients currently using metformin (metformin hydrochloride), other oral hypoglycemic
agents or insulin

- Patients with any history of allergic reaction to paclitaxel or other taxanes or
carboplatin

- Patients with a history of chronic kidney disease or lactic acidosis

- Patients with >= 10% weight loss within the past month

- Severe, active co-morbidity, defined as follows:

- Diagnosis of type I or type II diabetes mellitus

- Uncontrolled neuropathy >= grade 2 regardless of cause

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days of
registration

- Severe hepatic disease, defined as a diagnosis of Child-Pugh class B or C hepatic
disease

- Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4
count < 200 cells/microliter; note that patients who are HIV positive are
eligible, provided they are under treatment with highly active antiretroviral
therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior
to registration; note also that HIV testing is not required for eligibility for
this protocol

- End-stage renal disease (ie, on dialysis or dialysis has been recommended)

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception