Trametinib and Pembrolizumab in Treating Patients With Recurrent Non-small Cell Lung Cancer That Is Metastatic, Unresectable, or Locally Advanced

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PRIMARY OBJECTIVES: I. To evaluate the toxicity profile of trametinib, a MEK inhibitor, in combination with pembrolizumab, an anti PD-1 monoclonal antibody, as treatment for refractory to chemotherapy KRAS mutation positive (mut+) and KRAS wild-type patients with advanced non-small cell lung cancer ...

PRIMARY OBJECTIVES: I. To evaluate the toxicity profile of trametinib, a MEK inhibitor, in combination with pembrolizumab, an anti PD-1 monoclonal antibody, as treatment for refractory to chemotherapy KRAS mutation positive (mut+) and KRAS wild-type patients with advanced non-small cell lung cancer (NSCLC) and establish a recommended dose for the combination for the phase II portion of the study. (Part 1) II. To determine the 6-month overall response rate (ORR) for the combination of trametinib + pembrolizumab in subjects with NSCLC who received prior cytotoxic chemotherapy and anti-PD1 or anti-PD-L1 therapy. (Part 2) SECONDARY OBJECTIVES: I. To evaluate overall response rates (ORRs) using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1 and immune related [ir]RECIST) and duration of response (DOR), median progression free survival (PFS) and overall survival (OS) in KRAS mut+, KRAS wild-type, PD-L1+ and PD-L1 negative cohorts of patients. II. To evaluate ORRs by immune-related RECIST (irRECIST). III. To assess the safety and tolerability of pembrolizumab in combination with trametinib at the recommended dose to be used in future studies. IV. To characterize the pharmacokinetics of trametinib and pembrolizumab when administered in combination. V. To identify prognostic and predictive markers for the two treatment regimens by analyzing pre- and on-treatment tumor biopsies. EXPLORATORY OBJECTIVES: I. Evaluate exploratory genomic and gene expression biomarkers and their relationships in tumors in response to study treatment. II. Analyze circulating soluble factors including cytokines, chemokines, and antibodies against tumor and self antigens in response to clinical outcomes. III. Assess the activation state, quantity, and phenotype of T cells, B cells, and natural killer cells and the presence of immune regulatory cells (myeloid-derived suppressor cells) (MDSC) in response to treatment. IV. Examine changes in the localization and numbers of tumor infiltrating lymphocytes (TILs) expressing key markers (PD-1, CD8, CD4, CD45RO, granzyme, CD68, Foxp3) by immunohistochemistry in response to treatment. V. Perform immune monitoring studies in tissue and blood and correlate with genomic profiling and outcomes including toxicities. VI. Evaluate KRAS-mutation specific T cell response in patients before and after monotherapy with PEMBROLIZUMAB and the combination of PEMBROLIZUMAB and trametinib. VII. Evaluate immunophenotypes within the context of subsets of KRAS co-mutations (KRAS/p53, KRAS/LKB1, KRAS/CDKN2A/B inactivation). VIII. Collect and store archival diagnostic tumor samples, matched pre- and post-treatment tumor biopsy samples and deoxyribonucleic acid (DNA) (from tumor and blood) for future exploratory research into genes/genetic variation and factors that may influence resistance and/or sensitivity, and/or response to trametinib and/or PEMBROLIZUMAB. IX. Explore the relationship between pharmacokinetic (PK) plasma trametinib levels, trametinib exposure, safety and clinical outcome measures. X. Isolate peripheral blood mononuclear cells (PBMCs) from whole blood to enable flow cytometric analysis of additional markers and perform functional testing for antigen specificity and responsiveness, and T cell receptor (TCR) diversity. XI. Perform flow cytometric analyses in tumor tissue. XII. Analysis of the host microbiome from stool. XIII. Analysis of micro ribonucleic acid (miRNA) platelets and analysis in response to study treatment. OUTLINE: This is a phase Ib, dose-escalation study of trametinib followed by a phase II study. Patients receive trametinib orally (PO) once daily (QD) 14 days prior to cycle 1 and days 1-10 of each course (10 days on, 11 days off). Beginning in cycle 2, participants also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and every 3 months for up to 3 years.

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