Phase I Study of Single Agent MK-3475 in Patients with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma
What is the purpose of this trial?
Primary Objectives 1) To evaluate and characterize the tolerability and safety profile of single agent MK-3475 in adult patients with unresectable advanced carcinoma (including NSCLC or MEL). Hypothesis: Intravenous administration of single agent MK-3475 will have acceptable safety and tolerability. 2) To evaluate anti-tumor activity of MK-3475 in MEL and NSCLC. Hypothesis: Single agent MK-3475 will show a clinically meaningful response rate (RR) or disease-control-rate (DCR) in ipilimumab-naïve MEL patients, a clinically meaningful RR in MEL patients previously treated with ipilimumab, a clinically meaningful RR in MEL patients refractory to ipilimumab, and a clinically meaningful RR in NSCLC patients that merits further investigation (for details 3) To evaluate the extent of tumor response that correlates with the degree of biomarker positivity in the tumors of ipilimumab naïve patients treated with MK-3475 with the intent that the cut point for the PD-L1 assay will be explored and refined with tumor samples from ipilimumab-naïve MEL. Hypothesis: We will be able to define a sub-population of ipilimumab-naïve MEL patients whose tumors express PD-L1. These patients will have a clinically meaningful tumor response compared to ipilimumab naïve MEL patients whose tumors do not express PD-L1. 4) To evaluate anti-tumor activity of MK-3475 in unselected MEL refractory to ipilimumab patients and MEL patients refractory to ipilimumab with PD-L1 expressing tumors. Hypothesis: Single agent MK-3475 will show a clinically meaningful response rate (RR) or disease-control-rate (DCR) in unselected MEL patients refractory to ipilimumab, however single agent MK-3475 will show a more clinically meaningful response rate (RR) or disease-control-rate (DCR) in MEL patients refractory to ipilimumab with PD-L1 expressing tumors. Secondary Objectives 1) To characterize the PK profile of single agent MK-3475. 2) To evaluate target engagement and modulation in peripheral blood (PD-1 receptor occupancy and modulation of receptor activity). 3) To investigate the relationship between candidate efficacy biomarkers and anti-tumor activity of MK-3475: To evaluate the correlation between PD-L1 expression levels and anti-tumor activity of MK-3475, excluding ipi-refractory patients as stated in the primary objectives. To investigate other biomarkers (e.g., tumor infiltrating lymphocytes, PD-L2, PD-1; ribonucleic acid (RNA) signature profiles) that may correlate with tumor responses. To evaluate differences in tumor tissue characteristics in biopsies taken during or post-treatment with MK-3475 versus baseline. 4) To evaluate response duration, progression-free-survival and overall survival of MEL patients who are treated with MK-3475. 5) To evaluate response duration, progression-free survival and overall survival of NSCLC patients who are treated with MK-3475. Tertiary Objectives 1) To examine concordance between archival tumor tissues, formalin-fixed, paraffinembedded tissue (FFPET) and fresh frozen tumor tissue with respect to PD-L1 expression and other candidate efficacy biomarkers.
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