This phase I trial studies the side effects, best dose, and best way to give pembrolizumab when given together with paclitaxel, carboplatin, and radiation therapy in treating patients with stage II-IIIB non-small cell lung cancer. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel and carboplatin, 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. Giving pembrolizumab together with paclitaxel, carboplatin, and radiation therapy may kill more tumor cells.
PRIMARY OBJECTIVES: I. To assess safety and toxicity of anti-programmed cell death 1 (PD-1) inhibition with pembrolizumab with concurrent chemoradiation therapy for non-operable, locally advanced non-small cell lung cancer. SECONDARY OBJECTIVES: I. To evaluate local control and distant metastasis-free survival, progression-free and overall survival with the addition of pembrolizumab to chemoradiotherapy. II. To evaluate the rates of pneumonitis that may result from combination pembrolizumab and chemoradiotherapy. TERTIARY OBJECTIVES: I. To assess whether programmed cell death ligand 1 (PDL1) status on immunohistochemistry is predictive of response to pembrolizumab when combined with chemoradiation therapy. II. To assess T cell (cluster of differentiation 8 positive \[CD8+\] T cells and CD4+ forkhead box P3 positive \[FoxP3+\] regulatory cells) responses at weeks 1, 3, 6 during chemoradiation therapy and before each administration of pembrolizumab for cycles 1, 2, 3. OUTLINE: This is a dose-escalation study of pembrolizumab. Patients receive paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Patients undergo 3-dimensional (3D) conformal radiation therapy (CRT) or intensity-modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6 weeks . Beginning 2-6 weeks after, 2 weeks before the end, or at the start of chemotherapy and radiation therapy , patients also receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days every 12 weeks for 1 year, every 16 weeks for 1 year, every 6 months for 3 years, and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
23
Undergo 3D-CRT or IMRT
Given IV
Undergo 3D-CRT or IMRT
Correlative studies
Given IV
Given IV
Yale Cancer Center
New Haven, Connecticut, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, United States
Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of the Combination of Pembrolizumab With Paclitaxel, Carboplatin and Radiation Therapy According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
The 3+3 algorithm design will be used to find the MTD. Safety will be evaluated by DLT, defined as grade 4 pneumonitis. Toxicities will be characterized based on seriousness, causality, toxicity grading, and action taken with regard to trial treatment.
Time frame: Up to 30 days
Overall Survival as Measured by the Kaplan Meier Estimation Method
Overall survival is the overall longevity of the patient from time of initiation of chemoradiation to time of death.
Time frame: Time of initiation of chemoradiation through study completion (death)
Best Overall Response According to Response Evaluation Criteria in Solid Tumors RECIST 1.1
Best response on treatment was based on RECIST 1.1. Complete response (CR) is complete disappearance of all target lesions; Partial Response (PR) is at least 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference baseline sum. Progressive disease(PD) is at least 20%increase in the sum of the longest diameter of target lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions or progression of non-target lesions. Stable disease is defined as any condition not meeting the above criteria.
Time frame: Time of initiation of chemoradiation through study completion (death)
Metastasis-free Survival as Measured by the Kaplan Meier Estimation Method
The length of time from the start of treatment and cancer has not spread to other parts of the body.
Time frame: Time of initiation of chemoradiation through study completion (death)
Progression Free Survival According Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as Measured by the Kaplan Meier Estimation Method
Progression-free survival is the event without sign of any progression either locally or distantly, measured from the initiation of chemoradiation. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target lesions and assessed by CT or MRI imaging: Complete response (CR) - disappearance of all target lesions; Partial response (PR) - \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) - At least a 20% increase in the sum of the longest diameter of target lesions; or Stable Disease (SD) - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Time of initiation of chemoradiation through study completion (death)
Immune-related Response Evaluation Criteria In Solid Tumors Using Immune-Related Response (irRC).
Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions for at least 4 weeks from the date of documentation of complete response. Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular diameters of all index lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the sum of the products of the two largest perpendicular diameters of all index lesions and of new measurable lesions are added together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is considered an immune Partial Response Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for immune complete response or immune partial response, in the absence of progressive disease
Time frame: Time of initiation of chemoradiation through study completion (death)
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