METformin With a Cargohydrate Restricted Diet in Combination With Platinum Based Chemotherapy in Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer

Metformin, an oral biguanide agent used for the treatment of non-insulin-dependent diabetes
mellitus, is now prescribed to more than 120 million people worldwide. Its glucose lowering
effects result from both inhibition of liver gluconeogenesis and increased insulin
sensitivity in peripheral tissue[5]. Metformin has limited adverse effects with little or no
risk of hypoglycemia in healthy, nondiabetic controls. In addition to its anti-diabetic
properties, metformin has demonstrated both chemopreventative and therapeutic effects in
both prostate and breast cancer.

The role of metformin as a preventative and therapeutic agent in lung cancer is beginning to
be assessed. A recent epidemiological study from Taiwan demonstrated a 39-45% decreased risk
of lung cancer in diabetic patients being treated with antidiabetic drugs including
metformin versus those not taking these agents[12]. These studies have triggered preclinical
and clinical observational trials that further support metformin's potential as an
antineoplastic agent. Two observational studies in humans have reinforced metformin's
potential role as a therapeutic agent in lung cancer. In the first, Mezzone et al. showed
that diabetic patients with lung cancer previously treated with metformin or
thiazolidinediones had a lower incidence of metastatic disease at the time of diagnosis and
a reduced risk of death compared to those who did not receive the same treatment[15]. More
recently, a retrospective study performed by Tan et al. evaluated the outcomes of three
groups of diabetic patients with NSCLC treated with first line chemotherapy and receiving
various diabetic drugs. In this study, patients treated with chemotherapy with metformin had
superior outcomes compared to those patients treated with chemotherapy with insulin or with
drugs other than metformin (OS, 20 months vs. 13.1 months vs 13.0 months, respectively,
p=0.007)[16]. The remarkable activity of this agent in both preclinical and clinical lung
cancer models as well as its low toxicity and tolerability in non- diabetic patients
warrants further prospective studies evaluating the therapeutic efficacy with platinum based
chemotherapy in NSCLC.

Inclusion Criteria:

- • Able to provide written consent and is amenable to compliance with protocol
schedules and testing

- Subject is > 18 years of age

- Pathologically proven (either histologic or cytologic) diagnosis of Stage IIIB
or IV non-squamous non-small cell lung cancer

- No prior, palliative chemotherapy for stage IV lung cancer Subjects who have
received adjuvant chemotherapy post surgery for curative intent more than 12
months prior to development of stage IV disease are allowed.

- Measurable disease as RECIST criteria 1.1 (Response Evaluation Criteria in Solid
Tumors, Version 1.1)

- CT Scan of the chest/abdomen/pelvis or PET Scan within 30 days of study entry

- An MRI of the brain or Head CT Scan with contrast within 30 days of study entry
if clinically indicated

- ECOG Performance Status 0-2.

- CBC/differential obtained within 2 weeks prior to registration on study, with
adequate bone marrow function defined as follows:

- Absolute neutrophil count (ANC) >1,500 cells/ul

- Platelets > 100,000 cells/ul

- Hemoglobin > 9.0 g/dl (Note: The use of transfusion or other intervention
to achieve Hgb > g/dl is acceptable.)

- Serum creatinine < 1.5 x ULN

- Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN)

- AST and ALT < 3.0 x the ULN

- Women of childbearing potential must have:

- A negative serum or urine pregnancy test (sensitivity 14 days prior to the start of study drug administration

- Persons of reproductive potential must agree to use and utilize an adequate
method of contraception throughout treatment and for at least 90 days after
study drug is stopped prior to study enrollment, women of childbearing
potential must be advised of the importance of avoiding pregnancy during
trial participation and the potential risk factors for an unintentional
pregnancy.

- Ability to take oral medication

Exclusion Criteria:

- • The subject has a diagnosis of squamous cell carcinoma. Adenosquamous (mixed)
histologies are allowed

- The subject has a history of type I or type II diabetes

- Weight of less than 80% of (IBW) ideal body weight

- Creatinine clearance less than 45 l/min as calculated by the Cockcroft-Gault
equation

- Known EGFR or ALK mutation in which targeted therapy with erlotinib or
crizotinib would be the standard of care. Those subjects whose tissue is not
tested or have insufficient material are eligible

- The subject is currently taking or has previously taken metformin in the past 6
months

- The subject has received previous chemotherapy for NSCLC except in instances of
adjuvant therapy post surgical resection more than 12 months prior to enrollment

- The subject has undergone major surgery within four weeks prior to
randomization.

- The subject has undergone palliative radiation (chest, brain) to tumor sites
within two weeks of randomization (except palliative radiation to the bone which
can be within one week

- Uncontrolled (untreated) brain metastasis.

- Subject who has NCI-CTCAE Version 4 Grade > 2 diarrhea

- That subject has clinically relevant CAD or uncontrolled CHF

- The subject has ongoing or active infection (requiring antibiotics) that would
limit the administration of chemotherapy including active TB. HIV is allowed in
this study

- The subject has a history of neurological or psychological disorder that may
interfere with the compliance of the protocol

- Women who are unwilling or unable to use an acceptable method to avoid pregnancy
for the entire study period and for at least 4 weeks after cessation of study
drug, or have a positive pregnancy test at baseline, or are pregnant or
breastfeeding