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

Stage IV Lung Cancer AJCC v8 Clinical Trial

Official title: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer - (IM-BATTLE-2 Program)

Status Active, not recruiting

Clinical Trial Summary

This phase Ib/II trial studies the side effects and best dose of trametinib when given together with pembrolizumab and to see how well they work in treating patients with non-small cell lung cancer that has come back and spread to other places in the body, cannot be removed by surgery, or spread to nearby tissues or lymph nodes. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving trametinib and pembrolizumab may work better in treating patients with non-small cell lung cancer.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Metastatic Lung Non-Small Cell Carcinoma
• Recurrent Lung Non-Small Cell Carcinoma
• Stage III Lung Cancer AJCC v8
• Stage IIIA Lung Cancer AJCC v8
• Stage IIIB Lung Cancer AJCC v8
• Stage IIIC Lung Cancer AJCC v8
• Stage IV Lung Cancer AJCC v8
• Stage IVA Lung Cancer AJCC v8
• Stage IVB Lung Cancer AJCC v8
• Unresectable Lung Non-Small Cell Carcinoma

• NCT number: NCT03225664
• Study type: Interventional
• Source: M.D. Anderson Cancer Center
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: February 3, 2018
• Completion date: December 31, 2024