The purpose of this study is to determine the feasibility and evaluate the safety of delivering chemoradiotherapy, the usual approach to non-small cell lung cancer, in combination with pembrolizumab (MK-3745), followed by consolidation pembrolizumab after surgical resection. Consolidation therapy is treatment given following the initial treatment. Pembrolizumab is an investigational drug (also known as Keytruda), which has been approved by the FDA for use in certain types of skin cancer (melanoma), and for use in certain types of head and neck cancer. However, it has not been approved for use in other cancers such as non-small cell lung cancer (NSCLC). Pembrolizumab is a monoclonal antibody that binds to the surface of some cells of the immune system and activates them against cancer cells. It is not chemotherapy.
The primary hypothesis is that the addition of pembrolizumab to neoadjuvant concurrent chemoradiation, followed by consolidation pembrolizumab, will be safe and feasible to deliver to patients with resectable stage 3A Non-small cell lung cancer (NSCLC). This study also plans to observe the efficacy of this combination in the overall and biomarker-positive population. Primary Objective Primary objective of this phase 1 study is to determine safety and feasibility of MK3475 with standard of care therapy of chemotherapy with radiation for newly diagnosed stage 3 lung carcinoma. • To define the Safety, tolerability and feasibility of MK3475 in combination with chemotherapy with cisplatin and etoposide along with 45 Gy of radiation in newly diagnosed stage 3 non-small cell lung carcinoma. Secondary Objective(s) * Progression Free Survival * Objective response rate, * Complete pathologic response rate, * Nodal downstaging at surgery, * Overall survival, * Safety and tolerability Correlative Objective(s) Exploratory objectives: Overall response rate, progression free survival, overall survival in Programmed death-ligand (PDL-1) positive versus negative subgroups Study Design This is an open-label, single arm phase I trial of neoadjuvant chemotherapy + pembrolizumab with concurrent radiation followed by surgical resection and consolidation pembrolizumab in resectable stage 3A (N2+) NSCLC. Eligible patients will have biopsy-confirmed T1-3N2M0 (stage IIIA) non-small cell lung cancer (adenocarcinoma, squamous cell carcinoma, or large cell/NSCLC not otherwise specified), performance status 0-1, adequate lung function and deemed medically resectable by a thoracic surgeon, adequate organ function for chemotherapy, and no contraindications to pembrolizumab (i.e. autoimmune disorders or underlying pulmonary fibrosis). Because pembrolizumab has been safely added to multiple platinum doublet chemotherapy regimens in lung cancer but not yet tested in the setting of concurrent radiation, we plan to evaluate safety and feasibility of the combination therapy. 10 patients will be enrolled at the full starting dose of all 3 agents. If 3 or more (\>30%) have grade 3 or higher pulmonary toxicity or any grade 4 nonhematologic toxicity, the study will be stopped. If 2 or fewer have \> grade 3 pulmonary toxicity or \> grade 4 other nonhematologic toxicity, then an additional 10 will be enrolled. If 5 or fewer (\<25%) of the 20 patients have \> grade 3 pulmonary toxicity or \> grade 4 other nonhematologic toxicity, then this regimen will be deemed safe and feasible for further study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
9
Cisplatin (50mg/m2 IV D1, 8, 29, 36)
Etoposide (50mg/m2 IV D1-5, 29-33)
Pembrolizumab (200mg IV D1, 21, 42)
Radiation (1.8Gy/D to 45Gy in 25 fractions)
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
Number of patients with grade 3 pulmonary toxicity or grade 4 other non hematologic toxicity
If 5 or fewer (\<25%) of the 20 patients have \> grade 3 pulmonary toxicity or \> grade 4 other nonhematologic toxicity, then this regimen will be deemed safe and feasible for further study
Time frame: Up to 5 years
Progression Free Survival
Time from beginning of treatment to progression, death, or five years, whichever came first. Progression is defined as Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm
Time frame: Up to 5 years
Objective Response Rate
Number of patients with objective response (CR + PR) where complete response is defined as Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. And Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to 5 years
Complete Pathologic Response Rate
Pathological complete response is defined as absence of foci of tumor cells at the local site (pCR)
Time frame: Up to 5 years
Nodal Downstaging at Surgery
Number of patients with reduced stages in nodes at surgery
Time frame: Up to 4 weeks after induction treatment
Overall Survival
Time from beginning of treatment to death or 5 year, whichever comes first
Time frame: Up to 5 years
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