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Paclitaxel, Carboplatin, and Bevacizumab With or Without Metformin Hydrochloride in Treating Patients With Previously Untreated Stage IV Non-Small Cell Lung Cancer

Trial Status: Administratively Complete

This randomized phase II trial studies how well paclitaxel, carboplatin, and bevacizumab with or without metformin hydrochloride works in treating patients with previously untreated stage IV non-small cell lung cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin and metformin hydrochloride, works in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether paclitaxel, carboplatin, and bevacizumab is more effective with or without metformin hydrochloride in treating non-small cell lung cancer.

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 must have a life expectancy of greater than 12 weeks
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [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 International Normalized Ratio (INR) < 1.5 and a partial thromboplastin time (PTT) no greater than upper limits of normal within 1 week prior to randomization
  • Patients with a history of hypertension must be well-controlled (< 150 systolic/< 100 diastolic) 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; caution should be taken on treating patients with low dose heparin or low molecular weight heparin for deep vein thrombosis (DVT) prophylaxis during treatment with bevacizumab as there may be an increased risk of bleeding
  • Prior use of chemotherapy (targeted therapy such as erlotinib and crizotinib will be allowed; if a patient was receiving erlotinib and/ or crizotinib as targeted therapy before entering the study they should discontinue that medication 2 weeks before day 1 of the study)
  • 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
  • Patients that are human immunodeficiency virus (HIV)-positive on combination antiretroviral therapy
  • Patients with a history of or with a current diagnosis of diabetes mellitus
  • Patients taking Metformin for any reason within 30 days of enrollment to the study

Maryland

Baltimore
Johns Hopkins Bayview Medical Center
Status: ADMINISTRATIVELY_COMPLETE
Contact: Phillip Andrew Dennis
Phone: 410-550-9250
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ADMINISTRATIVELY_COMPLETE
Contact: David S. Ettinger
Phone: 410-955-8847

PRIMARY OBJECTIVES:

I. To evaluate the 1 year progression-free survival (PFS) of the combination of carboplatin, paclitaxel, bevacizumab with metformin versus carboplatin paclitaxel and bevacizumab in patients that are chemotherapy naïve (erlotinib and crizotinib will be allowed) with advanced or metastatic pulmonary adenocarcinoma.

SECONDARY OBJECTIVES:

I. To evaluate the response to therapy and overall survival of the combination of metformin with standard chemotherapy in patients that are chemotherapy naïve (erlotinib and crizotinib will be allowed) with advanced or metastatic pulmonary adenocarcinoma.

II. To determine whether liver kinase B1 (LKB1) gene status in tumors is a significant determinant of response when metformin is added to the therapy.

III. To acquire preliminary data regarding the effects of metformin on uptake of fluorodeoxyglucose in tumor and normal tissues.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

INDUCTION THERAPY

ARM A: Patients receive metformin hydrochloride orally (PO) twice daily (BID). Patients also receive paclitaxel intravenously (IV) over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1.

ARM B: Patients receive paclitaxel IV, carboplatin IV, and bevacizumab IV as in Arm A.

In both arms, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients achieving complete response, partial response, or stable disease receive metformin hydrochloride PO BID and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
David S. Ettinger

  • Primary ID J1188
  • Secondary IDs NCI-2012-00856, NA_00052073
  • Clinicaltrials.gov ID NCT01578551