Metformin and Carbohydrate Restriction With Platinum Based Chemotherapy In Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NS-NSCLC)
Condition: Non-small Cell Lung Cancer Stage IIIB/IV; Non-small Cell Lung Cancer Metastatic; Nonsquamous Nonsmall Cell Neoplasm of Lung
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: metformin; carbohydrate restricted diet
Intervention description: Addition of metformin 1000 mg po bid to standard of care platinum based chemotherapy; addition of dietary counseling and metformin 1000 mg po bid to platinum based chemotherapy
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: non squamous; non small cell; lung cancer; metformin

Summary:

      Metformin is thought to activate AMP-activated protein kinase (AMPK), a major sensor of
      cellular energy levels and a key enzyme limiting cellular growth during times of cellular
      stress. Once activated, this enzyme restricts anabolic processes such as protein, cholesterol
      and fatty acid synthesis and inhibits mTOR, a protein kinase responsible for unregulated
      growth. MTOR is upregulated in a variety of tumors, including NSCLC providing rationale to
      take advantage of this pathway with metformin.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Able to provide written consent and is amenable to compliance with protocol schedules
             and testing

          2. Patient is > 18 years of age

          3. Pathologically proven (either histologic or cytologic) diagnosis of Stage IIIB or IV
             non-squamous non-small cell lung cancer

          4. No prior, palliative chemotherapy for stage IV lung cancer Patients who have received
             adjuvant chemotherapy post surgery for curative intent more than 12 months prior to
             development of stage IV disease are allowed.

          5. Measurable disease as RECIST criteria 1.1 (Response Evaluation Criteria in Solid
             Tumors, Version 1.1)

          6. CT Scan of the chest/abdomen/pelvis or PET Scan within 30 days of study entry

          7. An MRI of the brain or Head CT Scan with contrast within 30 days of study entry if
             clinically indicated

          8. ECOG Performance Status 0-2.

          9. 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.)

         10. Serum creatinine < 1.5 x ULN

         11. Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN)

         12. AST and ALT < 3.0 x the ULN

         13. 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.

         14. Ability to take oral medication

        Exclusion Criteria:

          1. The patient has a diagnosis of squamous cell carcinoma. Adenosquamous (mixed)
             histologies are allowed

          2. The patient has a history of type I or type II diabetes

          3. Weight of less than 80% of (IBW) ideal body weight

          4. Creatinine clearance less than 45 l/min as calculated by the Cockcroft-Gault equation

          5. Known EGFR or ALK mutation in which targeted therapy with erlotinib or crizotinib
             would be the standard of care. Those patients whose tissue is not tested or have
             insufficient material are eligible

          6. The patient is currently taking or has previously taken metformin in the past 6 months

          7. The patient has received previous chemotherapy for NSCLC except in instances of
             adjuvant therapy post surgical resection more than 12 months prior to enrollment

          8. The patient has undergone major surgery within four weeks prior to randomization.

          9. The patient 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

         10. Uncontrolled (untreated) brain metastasis.

         11. Patient who has NCI-CTCAE Version 4 Grade >= 2 diarrhea

         12. That patient has clinically relevant CAD or uncontrolled CHF

         13. The patient has ongoing or active infection (requiring antibiotics) that would limit
             the administration of chemotherapy including active TB. HIV is allowed in this study

         14. The patient has a history of neurological or psychological disorder that may interfere
             with the compliance of the protocol

         15. 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