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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02186847
Recruitment Status : Active, not recruiting
First Posted : July 10, 2014
Last Update Posted : September 5, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Tracking Information
First Submitted Date  ICMJE July 8, 2014
First Posted Date  ICMJE July 10, 2014
Last Update Posted Date September 5, 2019
Study Start Date  ICMJE August 2014
Actual Primary Completion Date April 16, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2015)
PFS [ Time Frame: Interval from randomization to progression or death due to any cause, whichever occurs first, assessed up to 5 years ]
PFS rates will be estimated using the Kaplan-Meier method, and the differences between arms will be tested using a log-rank test. A multivariate analysis with the Cox proportional hazard model for PFS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting for patient-specific risk factors.
Original Primary Outcome Measures  ICMJE
 (submitted: July 8, 2014)
Progression Free Survival (PFS) [ Time Frame: Interval from randomization to progression or death due to any cause, whichever occurs first, assessed up to 5 years ]
PFS rates will be estimated using the Kaplan-Meier method, and the differences between arms will be tested using a log-rank test. A multivariate analysis with the Cox proportional hazard model for PFS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting for patient-specific risk factors.
Change History Complete list of historical versions of study NCT02186847 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2016)
  • OS [ Time Frame: Interval from randomization to death due to any cause, assessed up to 5 years ]
    OS is analyzed as time-to-event data, where the OS rates will be estimated using the Kaplan-Meier method, and the differences between treatment arms will be tested using the log-rank test.
  • Rate of treatment-related adverse events using National Cancer Institution (NCI) CTCAE, v. 4 [ Time Frame: Within 1 year of completion of all treatment ]
    Will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm, and analyzed using Chi-square test or Fisher's exact test wherever applicable. The analysis will be performed at the time of primary endpoint analysis. Logistic regression will be used to model the distribution of adverse events with and without adjustment for covariates. Both unadjusted and adjusted odds ratios and the respective 95% confidence intervals will be computed and tested at a significance level of 0.05 (2-sided).
  • Time to DM [ Time Frame: Interval from randomization to distant metastasis, assessed up to 5 years ]
    Only distant metastasis will be counted as events, and deaths or local-regional progression without distant metastasis will be treated as competing risks. A cumulative incidence approach will be used to estimate the respective rates, and the corresponding differences in LRP and DM will be evaluated using Gray's test.
  • Time to LRP [ Time Frame: Interval from randomization to local or regional progression, assessed up to 5 years ]
    A competing risks analysis approach will be used when analyzing time to LRP. Only local-regional progression will be counted as events (failures), and patients who die or have a distant metastasis without a local-regional progression will be treated as competing risk. A cumulative incidence approach will be used to estimate the respective rates, and the corresponding differences in LRP and DM will be evaluated using Gray's test.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2014)
  • Overall Survival (OS) [ Time Frame: Interval from randomization to death due to any cause, assessed up to 5 years ]
    OS is analyzed as time-to-event data, where the OS rates will be estimated using the Kaplan-Meier method, and the differences between treatment arms will be tested using the log-rank test.
  • Time to Local Regional Progression (LRP) [ Time Frame: Interval from randomization to local or regional progression, assessed up to 5 years ]
    A competing risks analysis approach will be used when analyzing time to LRP. Only local-regional progression will be counted as events (failures), and patients who die or have a distant metastasis without a local-regional progression will be treated as competing risk. A cumulative incidence approach will be used to estimate the respective rates, and the corresponding differences in LRP and DM will be evaluated using Gray's test.
  • Time to Disease Metastasis (DM) [ Time Frame: Interval from randomization to distant metastasis, assessed up to 5 years ]
    Only distant metastasis will be counted as events, and deaths or local-regional progression without distant metastasis will be treated as competing risks. A cumulative incidence approach will be used to estimate the respective rates, and the corresponding differences in LRP and DM will be evaluated using Gray's test.
  • Rate of treatment-related adverse events using National Cancer Institution (NCI) CTCAE, v. 4 [ Time Frame: Within 1 year of completion of all treatment ]
    Will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm, and analyzed using Chi-square test or Fisher's exact test wherever applicable. The analysis will be performed at the time of primary endpoint analysis. Logistic regression will be used to model the distribution of adverse events with and without adjustment for covariates. Both unadjusted and adjusted odds ratios and the respective 95% confidence intervals will be computed and tested at a significance level of 0.05 (2-sided).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer
Official Title  ICMJE Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC
Brief Summary 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

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.

ARM I: Patients receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36 and undergo radiation therapy (3-dimensional conformal radiation therapy [3D-CRT] or intensity modulated radiation therapy [IMRT]) once daily (QD) 5 days a week for 6 weeks. Beginning 28-42 days after completion of radiation therapy, patients receive consolidation chemotherapy comprising paclitaxel IV and carboplatin IV on days 1 and 22. Treatment with consolidation chemotherapy repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive metformin hydrochloride orally (PO) twice daily (BID) or thrice daily (TID) for 14 days. Beginning on day 15, patients undergo radiation therapy and receive paclitaxel and carboplatin as in Arm I, and receive metformin hydrochloride BID or TID for 6 weeks. Beginning 28-42 days after completion of radiation therapy, patients receive consolidation chemotherapy as in Arm I and metformin hydrochloride PO BID or TID for 10 weeks.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • Radiation: 3-Dimensional Conformal Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • 3-dimensional radiation therapy
    • 3D-CRT
    • Conformal Therapy
    • Radiation Conformal Therapy
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplat
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Metformin Hydrochloride
    Given PO
    Other Names:
    • Glucophage
    • Metformin HCl
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Radiation: Volume Modulated Arc Therapy
    Undergo radiation therapy
    Other Name: VMAT
Study Arms  ICMJE
  • Active Comparator: Arm I (chemoradiotherapy)
    Patients receive paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36 and undergo radiation therapy (3D-CRT or IMRT) QD 5 days a week for 6 weeks. Beginning 28-42 days after completion of radiation therapy, patients receive consolidation chemotherapy comprising paclitaxel IV and carboplatin IV on days 1 and 22. Treatment with consolidation chemotherapy repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Drug: Carboplatin
    • Radiation: Intensity-Modulated Radiation Therapy
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Radiation: Volume Modulated Arc Therapy
  • Experimental: Arm II (chemoradiotherapy, metformin hydrochloride)
    Patients receive metformin hydrochloride PO BID or TID for 14 days. Beginning on day 15, patients undergo radiation therapy and receive paclitaxel and carboplatin as in Arm I and receive metformin hydrochloride BID or TID for 6 weeks. Beginning 28-42 days after completion of radiation therapy, patients receive consolidation chemotherapy as in Arm I and metformin hydrochloride PO BID or TID for 10 weeks.
    Interventions:
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Drug: Carboplatin
    • Radiation: Intensity-Modulated Radiation Therapy
    • Other: Laboratory Biomarker Analysis
    • Drug: Metformin Hydrochloride
    • Drug: Paclitaxel
    • Radiation: Volume Modulated Arc Therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 8, 2014)
168
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 16, 2024
Actual Primary Completion Date April 16, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 [NOS])
  • 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 [BSA], 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 F 18 (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
  • 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)
  • Serum creatinine within normal institutional limits or creatinine clearance must be at least 60 ml/min
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for the institution
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN for the institution
  • 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
  • Patient must provide study specific informed consent prior to study entry

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Israel,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02186847
Other Study ID Numbers  ICMJE NRG-LU001
NCI-2014-01071 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PNRG-LU001_A01PAMDREVW01
NRG-LU001 ( Other Identifier: NRG Oncology )
NRG-LU001 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party NRG Oncology
Study Sponsor  ICMJE NRG Oncology
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Theodoros Tsakiridis NRG Oncology
PRS Account NRG Oncology
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP