Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma.
Condition: Carcinoma, Non-Small-Cell Lung; Lung Adenocarcinoma
MeSH terms: Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma of Lung
Intervention: Paclitaxel; Carboplatin; Bevacizumab; Metformin
Intervention description: 200 mg/m² IV over 3 hours, day 1 of each cycle. Paclitaxel + Carboplatin + Bevacizumab will be administered once every 21 days (Day 1) for up to 6 cycles. If subject has complete response, partial response, stable disease, or unacceptable toxicity. Bevacizumab with Metformin (Arm A) or Bevacizumab alone (Arm B) may continue as maintenance therapy.; Carboplatin is administered at AUC= 6 mg/ml X min IV over 15-30 minutes, immediately following Paclitaxel infusion every 21 days
Paclitaxel + Carboplatin + Bevacizumab will be administered once every 21 days (Day 1) for up to 6 cycles. If subject has complete response, partial response, stable disease, or unacceptable toxicity. Bevacizumab with Metformin (Arm A) or Bevacizumab alone (Arm B) may continue as maintenance therapy; All patients will receive the drug at 15 mg/kg every 21 days, given immediately after completion of chemotherapy, starting with Cycle 1. After induction chemotherapy is completed (4 cycles), bevacizumab will continue at 15 mg/kg every 21 days until PD (provided neither PD nor toxicity requiring discontinuation has occurred) measured from date of first dose of bevacizumab.; 1000 mg twice daily with food.
Intervention MeSH terms: Metformin; Biguanides; Paclitaxel; Bevacizumab; Carboplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Carcinoma, Non-Small-Cell Lung; Lung adenocarcinoma

Summary:

      To determine the 1 year progression-free survival (PFS) of the combination of metformin and
      standard chemotherapy in patients with previously untreated advanced or metastatic pulmonary
      adenocarcinoma.
    

Eligibility criteria:

        Inclusion Criteria:

        Patients must have Histologically or cytologically confirmed non-squamous cell, non small
        cell carcinoma of the lung.

        Patient must have measurable stage IV disease (includes M1a, M1b stages or recurrent
        disease) (according to the 7th edition of the 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.

        Patients must have a Life Expectancy of greater than 12 weeks.

        Patients must have an ECOG performance status 0 or 1 (Karnofsky > 70%; see Appendix A).

        Patients must have normal organ and marrow function as defined below, within one week prior
        to randomization:

          -  absolute neutrophil count >1,500/mcL

          -  platelets > 100,000/mcL

          -  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 INR < 1.5 and a PTT no greater than upper limits of normal within 1
        week prior to randomization.

        Patients with a history of hypertension must be well-controlled (<150sytolic/<100diastolic)
        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 a history of gross hemoptysis (defined as bright red blood of ½ teaspoon or
        more) will be excluded from this trial.

        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 with a history of thrombotic or hemorrhagic disorders.

        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 a serious non-healing wound ulcer, or bone fracture, or major surgical
        procedure within 21 days prior to starting treatment.

        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.