Background: Malignant peripheral nerve sheath tumors (MPNSTs) are generally resistant to chemotherapy. Receptor tyrosine kinases (RTKs) play a role in MPNST growth and include c-KIT, PDGFR, and CSF1R, all of which are inhibited by pexidartinib (PLX3397, PEX). We reported that the combination of PEX and the mTOR inhibitor sirolimus (S) synergistically inhibited MPNST growth (Patwardhan P. et al CCR 20: 3146, 2014). Inhibiting CSF1R resulted in a marked depletion of tumor-associated macrophages (TAMs) in MPNST xenografts and a shift from M2 (tumor promoting) to M1 (tumor inhibiting) TAMs within tumors. This effect on TAMs was enhanced and sustained by mTOR inhibition with S. Therefore, this drug combination, by potently blocking RTKs and by altering tumor macrophage infiltration, represents a novel drug combination. The goal of this first-in-man trial is to prove safety and test efficacy of PEX and S in sarcomas and MPNST. Methods: This is an open label, multicenter, investigator-initiated study testing PEX in combination with S in patients with advanced sarcomas (phase 1, N = 24) and MPNST (phase 2, N = 25). The primary objective of the phase 1 component is to determine the safety, tolerability, and the recommended phase 2 dose (RP2D) using the time-to-event continual reassessment method. The phase 1 component enrolls patients with sarcoma who have progressed on standard of care therapy or for whom no standard treatment exists. The primary outcome for phase 2 is progression free survival (PFS). Assuming a median PFS of 6 weeks in patients treated with standard of care, we have 90% power to detect a difference of 12 weeks in median PFS given a 2-sided test with an alpha of 0.05. Secondary objectives include response rate and overall survival. Patients enrolled to the phase 2 component will undergo mandatory biopsies at baseline and at end of cycle 1 and an optional biopsy on progression. Exploratory studies include analysis of RTK activity and assessment of TAMs within the tumor samples. This trial has started in December 2015 and has enrolled 4 patients to the phase Ib (2 PVNS, 1 MPNST, and 1 Epithelioid sarcoma) as of January 2016. Clinical trial information: NCT02584647