Phase 1/2a study of double immune suppression blockade by combining a CSF1R inhibitor (pexidartinib/PLX3397) with an anti PD-1 antibody (pembrolizumab) to treat advanced melanoma and other solid tumors.

Abstract

TPS465 Background: Tumor-associated macrophages (TAMs) support tumor growth and cause tumor resistance to chemotherapy and radiation therapy; myeloid-derived suppressor cells (MDSCs) suppress anti-tumor immunity and cause resistance to PD-1 inhibition. TAMs and MDSCs are both regulated by colony stimulating factor 1 (CSF1). Pexidartinib is a small molecule inhibitor of CSF1 receptor, CSF1R. The normal function of PD-1, expressed on the cell surface of activated T-cells, is to suppress excessive immune responses, eg, autoimmune reactions. Tumors utilize PD-1 signaling to downregulate immune-mediated elimination. Pembrolizumab is a potent, highly selective humanized monoclonal antibody that blocks interactions between PD-1 and its ligands, PD-L1 and PD-L2. We present the study design for a Phase 1/2a clinical trial assessing safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of pexidartinib and pembrolizumab in advanced solid tumors (NCT02452424). Methods: In Part 1 of this open-label, uncontrolled trial, patients with advanced solid tumors will receive pembrolizumab (200 mg IV q 3 weeks) and escalating daily oral doses of pexidartinib to establish the safety and tolerability of the combination and a recommended phase 2 dose (RP2D). In Part 2, the combination RP2D will be studied in an expanded panel of solid tumor cohorts in up to 475 patients, to assess safety and preliminary efficacy. The panel will include GI malignancies for which preclinical data support this combination, including gastric and gastro-esophageal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, and GI stromal tumors. Overall response rate (RECISTv1.1) and progression free survival will be evaluated. Exploratory endpoints include novel biomarkers of clinical activity and drug mechanisms of action. A truncated sequential probability ratio test will be employed in each tumor cohort to allow early decision-making for futility or success. The results will support further development of the pexidartinib/pembrolizumab combination in the solid tumors that respond to treatment in this study. Clinical trial information: NCT02452424.