This phase I trial studies the side effects and the best dose of trametinib when given together with combination chemotherapy and radiation therapy in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving trametinib, combination chemotherapy, and radiation therapy may be a better treatment for non-small cell lung cancer.
PRIMARY OBJECTIVES: I. Determine the maximum-tolerated dose (MTD) of GSK1120212 (trametinib) combined with standard chemoradiation in unresectable non-small cell lung cancer (NSCLC) and safety as measured by the rate of grade 3 or worse non-hematological toxicities occurring prior to the beginning of consolidation therapy (including all toxicities attributed to chemoradiation occurring within 10 weeks of the start of radiation therapy). II. Pharmacokinetic (PK) analysis of carboplatin, paclitaxel, and trametinib. SECONDARY OBJECTIVES: I. Response rate based on computed tomography (CT) or fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT imaging response assessment after completion of chemoradiation. II. Biomarker correlate to response and resistance. III. Overall survival. IV. Patterns of recurrence. V. Determine dose delay and the percentage of dose delivered for each agent. OUTLINE: This is a dose-escalation study of trametinib. CONCURRENT CHEMOTHERAPY: Patients undergo intensity-modulated radiation therapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) once daily (QD) 5 days a week for 6 weeks. Patients receive trametinib orally (PO) QD and carboplatin intravenously (IV) over 30 minutes and paclitaxel IV over 1 hour once weekly. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients without disease progression after completion of chemoradiation proceed to consolidation chemotherapy. CONSOLIDATION CHEMOTHERAPY: Beginning 3 weeks after completion of concurrent chemoradiation, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on days 1 and 22. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
16
Undergo 3D-CRT
Given IV
Undergo IGRT
Undergo IMRT
Correlative studies
Given IV
Correlative studies
Given PO
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Case Western Reserve University
Cleveland, Ohio, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
M D Anderson Cancer Center
Houston, Texas, United States
University of Wisconsin Carbone Cancer Center
Madison, Wisconsin, United States
Dose limiting toxicity defined as any grade 3 or 4 non-hematologic toxicities according to Common Terminology Criteria for Adverse Events version 4.0 grading
Toxicity will be tabulated by dose, type, and grade. The probability of toxicity over 70 days as a function of dose will be estimated by fitting a Bayesian binary outcome regression model.
Time frame: Within 70 days from the start of radiation therapy
Pharmacokinetic parameters of carboplatin and paclitaxel with the dosing of trametinib
Time frame: At 15 and 30 minutes prior to the start of infusion and then at 30 minutes, 4, 10, and 24 hours after infusion on day 15
Response rate based on CT or FDG-PET/CT imaging response assessment after completion of chemoradiation
Response rate will be estimated and 95% confidence interval will be provided.
Time frame: Up to 4 years
Overall survival (OS)
Unadjusted OS will be estimated by the Kaplan and Meier method.
Time frame: Up to 4 years
Patterns of recurrence
Relapse-free survival will be estimated by the Kaplan and Meier method.
Time frame: Up to 4 years
KRAS mutation status
KRAS and other biomarkers will be compared between pre-treatment tumors and recurrent tumors.
Time frame: Baseline
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