Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well chemotherapy and radiation therapy given with or without metformin hydrochloride works in treating patients with stage III non-small cell lung cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Metformin hydrochloride may shrink tumors and keep them from coming back. It is not yet known whether chemotherapy and radiation therapy is more effective when given with or without metformin hydrochloride in treating stage III non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether metformin hydrochloride (MET) added to chemoradiotherapy can improve progression-free survival (PFS) in patients with locally advanced non-small cell lung cancer (NSCLC). SECONDARY OBJECTIVES: I. Determine the effects of MET on overall survival (OS), time to local-regional progression (LRP), and time to distant metastasis (DM). II. Evaluate the effect of MET on chemoradiotherapy toxicity (Common Terminology Criteria for Adverse Events, version 4 [CTCAE, v. 4]) within 1 year of completion of all treatment. III. Collect biospecimens to develop biomarkers of MET activity. OUTLINE: Patients are randomized to 1 of 2 treatment arms. After completion of study treatment, patients are followed up at 4-6 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
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Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC

Conditions
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Adenosquamous Lung Carcinoma, Bronchioloalveolar Carcinoma, Large Cell Lung Carcinoma, Lung Adenocarcinoma, Non-Small Cell Lung Carcinoma, Recurrent Non-Small Cell Lung Carcinoma, Squamous Cell Lung Carcinoma, Stage IIIA Non-Small Cell Lung Cancer, Stage IIIB Non-Small Cell Lung Cancer

Intervention / Treatment
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* Radiation: Radiation Therapy
* Drug: Carboplatin
* Drug: Metformin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically or cytologically) proven diagnosis of stage IIIA or IIIB non-small cell lung cancer within 84 days of registration; eligible histologies include adenocarcinoma, adenosquamous, large cell carcinoma, squamous carcinoma, non-lobar and non-diffuse bronchoalveolar cell carcinoma or non-small cell lung cancer not otherwise specified) Patients must have measurable disease Patients must have unresectable disease, be medically inoperable, or unwilling to undergo surgical management Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: History/physical examination, including documentation of height, weight, body surface area, and vital signs, within 30 days prior to registration Computed tomography (CT) with IV contrast or magnetic resonance imaging (MRI) imaging (if CT scan with contrast is medically contraindicated) of the lung and upper abdomen through the adrenal glands, required within 45 days prior to registration (recommended within 30 days prior to registration MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 45 days prior to registration; note: the use of intravenous contrast is required for the MRI or CT; an MRI without contrast is only permitted if the patient has a contrast allergy Whole-body fludeoxyglucose (FDG)-positron emission tomography (PET)/CT required within 45 days prior to registration (recommended within 30 days prior to registration; note: patients do not need to have a separate CT of the chest and upper abdomen with contrast if PET/CT imaging includes a high quality CT with contrast Zubrod performance status 0-1 Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 Complete blood count(CBC)/differential obtained within 14 days prior to registration on study, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 Platelets >= 100,000 cells/mm^3 Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) Adequate renal function within 14 days prior to registration, defined as serum creatinine within normal institutional limits or creatinine clearance must be at least 60 ml/min; Adequate hepatic function within 14 days prior to registration, defined as total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase ≤ 2.5 x ULN for the institution; Fasting blood glucose ≤ 125 mg/dL within 14 days prior to registration; Serum albumin > 3.0 g/dl within 14 days prior to registration; For women of childbearing potential, a serum pregnancy test within 72 hours prior to registration; Patients with post-obstructive pneumonia are eligible provided they no longer require intravenous antibiotics at registration; Patients must be at least 3 weeks from prior thoracotomy (if performed); If a pleural effusion is present, the following criteria must be met at registration to exclude malignant involvement (incurable M1a disease): When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative; Effusions that are minimal (i.e. not visible under ultrasound guidance) and that are too small to safely tap are eligible. Women of childbearing potential and male participants must practice adequate contraception throughout the study; Exclusion Criteria: Patients with mixed small cell and non-small cell histologies Patients with distant metastasis Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Patients currently using metformin (metformin hydrochloride), other oral hypoglycemic agents or insulin Patients with any history of allergic reaction to paclitaxel or other taxanes or carboplatin Patients with a history of chronic kidney disease or lactic acidosis Patients with >= 10% weight loss within the past month Severe, active co-morbidity, defined as follows: Diagnosis of type I or type II diabetes mellitus Uncontrolled neuropathy >= grade 2 regardless of cause Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within the last 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration Severe hepatic disease, defined as a diagnosis of Child-Pugh class B or C hepatic disease Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol End-stage renal disease (ie, on dialysis or dialysis has been recommended) Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: Chemoradiation<br>60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin | Radiation: Radiation Therapy<br>* Radiation therapy (RT) is given in 2 Gy fractions once daily 5 days per week to a total of 30 fractions and 60 Gy. Photons required; 3-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) permitted. Starts within 14 days of randomization (Chemoradiation arm) or 14 days after metformin starts (Chemoradiation + Metformin arm).<br>* Other names: IMRT;Drug: Carboplatin<br>* 2 AUC (area under the curve) via IV weekly on days 1, 8, 15, 22, 29, and 36 from start of radiation therapy. Two 21 day cycles of 6 AUC via IV starting 28-42 days after the end of radiation therapy.<br>Drug: Paclitaxel<br>* 50 mg/m2 via IV weekly on days 1, 8, 15, 22, 29, and 36 from start of radiation therapy. Two 21 day cycles of 200 mg/m2 via IV 28-42 days after the end of radiation therapy.<br>|
| Experimental: Metformin + Chemoradiation<br>Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin | Radiation: Radiation Therapy<br>* Radiation therapy (RT) is given in 2 Gy fractions once daily 5 days per week to a total of 30 fractions and 60 Gy. Photons required; 3-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) permitted. Starts within 14 days of randomization (Chemoradiation arm) or 14 days after metformin starts (Chemoradiation + Metformin arm).<br>* Other names: IMRT;Drug: Carboplatin<br>* 2 AUC (area under the curve) via IV weekly on days 1, 8, 15, 22, 29, and 36 from start of radiation therapy. Two 21 day cycles of 6 AUC via IV starting 28-42 days after the end of radiation therapy.<br>Drug: Metformin<br>* Metformin is taken orally. Dose escalation begins 2 weeks prior to the initiation of chemoradiation. 500 mg twice daily days 1-7 of metformin. 500 mg three times daily days 8-14 of metformin. Three times a day with the following dosage: 500mg in the morning, 1000mg at noon, and 500mg in the evening concurrent with chemoradiation and through consolidation chemotherapy (days 15-126 of metformin),<br>* Other names: Metformin Hydrochloride;Drug: Paclitaxel<br>* 50 mg/m2 via IV weekly on days 1, 8, 15, 22, 29, and 36 from start of radiation therapy. Two 21 day cycles of 200 mg/m2 via IV 28-42 days after the end of radiation therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Alive Without Progression (Progression-free Survival) | Progression is defined per RECIST v1.1 as change in a known lesion(s) meeting one of the following criteria: [1] At least a 20% increase in the sum of the longest diameter of target lesions such that the absolute increase must be > 5 mm. [2] Appearance of ≥1 new lesions. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 progression-free survival events were reported. | From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Alive (Overall Survival) | Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 progression-free survival events were reported. | From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months. | 
| Percentage of Participants With Local-regional Progression | Local-regional progression (LRP) is defined as progression within the planned treatment volume (PTV) or outside the PTV but within the same lobe(s) of the lung as the primary tumor or in regional lymph nodes. Progression is defined as change in a known lesion(s) meeting one of the following criteria: [1] ≥ 20% increase in the sum of the longest diameter of target lesions such that the absolute increase must be > 5 mm. [2] Appearance of ≥1 new lesions. LRP time is defined as time from randomization to the date of first LRP, death without LRP (competing risk), or last known follow-up (censored). LRP rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 LRP events were reported. | From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months. | 
| Percentage of Participants With Distant Metastases | Distant metastasis (DM) is defined as the appearance of ≥ 1 new lesions at any site (including pleural or pericardial effusion) outside of the following: the planned treatment volume, the same lobe(s) of the lung as the primary tumor, or regional lymph nodes. Time to DM is defined as time from randomization to the date of first DM, death without DM (competing risk), or last known follow-up (censored). DM rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 progression-free survival events were reported. | From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months. | 
| Percentage of Participants With Treatment-related Grade 3 or Higher Adverse Events | Adverse events (AE) were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to adverse event. Treatment-related is defined definitely, probably, or possibly related to treatment. | From start of treatment to last follow-up. Maximum follow-up at time of analysis was 47.2 months. |