Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma.

Study Overview
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Brief Summary
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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.

Detailed Description
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Primary Objectives 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. Secondary Objectives A. To evaluate the response to therapy and overall survival of the combination of metformin with standard chemotherapy in patients with previously untreated advanced or metastatic pulmonary adenocarcinoma. B. To determine whether LKB1 gene status in tumors is a significant determinant of response when metformin is added to the therapy C. To acquire preliminary data regarding the effects of metformin on uptake of fluorodeoxyglucose in tumor and normal tissues. Treatment will be administered on an outpatient basis. Induction Therapy (Step 1, Cycles 1-4) Metformin starting at a dose of 500 mg twice a day, orally with meals. After one week, increase the dose of metformin to 1000 mg as the first dose of the day and 500 mg as the second dose. After another week, increase to 1000 mg of metformin two times a day. Metformin treatment will be initiated one week before beginning chemotherapy, if possible, but chemotherapy will not be delayed for metformin loading. Paclitaxel 200 mg/m2 IV over 3 hours. For Paclitaxel pre-medication information Carboplatin AUC = 6 mg/ml IV over 15 - 30 minutes, immediately following paclitaxel infusion Bevacizumab 15 mg/kg IV infusion over 30 - 90 minutes Metformin will be administered continuously, beginning one week before beginning chemotherapy, if possible, but chemotherapy will not be delayed for metformin loading. The other three drugs (paclitaxel, carboplatin, and bevacizumab) will be administered on day 1 of each 21 day cycle. Maintenance Therapy Patients responding to this therapy will be maintained with metformin (1000 mg twice daily) and bevacizumab (15 mg/kg IV over 30-90 minutes on day 1 of each 21-day cycle). Duration of Therapy In the absence of treatment delays due to adverse events, treatment may continue until one of the following criteria applies: Disease progression, Intercurrent illness that prevents further administration of treatment, Unacceptable adverse events(s), Patient decides to withdraw from the study, or General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.

Official Title
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A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Previously Untreated Advanced/Metastatic Pulmonary Adenocarcinoma

Conditions
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Carcinoma, Non-Small-Cell Lung, Lung Adenocarcinoma

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Bevacizumab
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Paclitaxel, Carboplatin, Bevacizumab, and Metformin. Metformin starting at a dose of 500 mg twice a day, orally with meals. After one week, increase the dose of metformin to 1000 mg as the first dose of the day and 500 mg as the second dose. After another week, increase to 1000 mg of metformin two times a day. Metformin treatment will be initiated one week before beginning chemotherapy, if possible, but chemotherapy will not be delayed for metformin loading. | Drug: Paclitaxel<br>* 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.<br>* Other names: NSC 673089;Drug: Carboplatin<br>* 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<br>* Other names: Paraplatin;Drug: Bevacizumab<br>* 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.<br>* Other names: Recombinant Humanized Monoclonal Anti-VEGF Antibody;Drug: Metformin<br>* 1000 mg twice daily with food.<br>* Other names: glucophage;|
| Active Comparator: Arm B<br>Paclitaxel, Carboplatin, and Bevacizumab | Drug: Paclitaxel<br>* 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.<br>* Other names: NSC 673089;Drug: Carboplatin<br>* 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<br>* Other names: Paraplatin;Drug: Bevacizumab<br>* 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.<br>* Other names: Recombinant Humanized Monoclonal Anti-VEGF Antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Number of months without evidence of progression after 1 year of the combination of metformin and standard chemotherapy in patients with previously untreated advanced or metastatic pulmonary adenocarcinoma. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Therapy | Percentage of participants with complete or partial response to combination of metformin with standard chemotherapy in patients with previously untreated advanced or metastatic pulmonary adenocarcinoma as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 2 years | 
| Overall Survial | Number of months alive after 1 year of the combination of metformin with standard chemotherapy in patients with previously untreated advanced or metastatic pulmonary adenocarcinoma. | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Non-Small-Cell Lung, Lung adenocarcinoma