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 </=25IU HCG/L) within 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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Both |
| Healthy Volunteers: | No |
