Background: Refractory tumors remain a significant treatment challenge, and novel approaches targeting the tumor microenvironment may hold promise. Pexidartinib, an oral inhibitor of tyrosine kinases including CSF1R, KIT and FLT3, has activity in adults with tenosynovial giant cell tumor. Methods: We are conducting a phase 1 trial (NCT02390752) to determine the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK) of pexidartinib in patients (pts) 3-21 years old with refractory leukemias and solid tumors including NF1 PN. The MTD is based on cycle (C) 1 toxicities. Pexidartinib is given once daily continuously (1C = 28 days) at DL 1: 400 mg/m2/dose, 2: 600mg/m2/dose, or 3: 800 mg/ m²/dose. Response is assessed after C1 and then every other C, and for NF1 PN with volumetric MRI analysis after every 4 C. Results: Fourteen pts (8 M:6 F, median age 16 years, (range 4-21) with CNS tumors (n = 2), sarcomas (n = 7), peritoneal mesothelioma (n = 1), leukemia (n = 1), NF1 PN (n = 3) have enrolled at DL1 (n = 4), DL2 (n = 4) and DL3 (n = 6). No dose-limiting toxicities have been observed and 11 pts are evaluable for MTD determination (received ≥ 85% of pexidartinib doses in C1). Common non-DLT toxicities are fatigue, decrease in WBC, increase in creatinine kinase and serum amylase, headache, anorexia, vomiting, diarrhea, and hair hypopigmentation. Mean (SD) pexidartinib C1 day 1 PK parameters at [DL1 (n = 4), DL2 (n = 4), and DL3 (n = 4)] were: C_max DL1 2,813 ng/mL (1,483), DL2 6,065 ng/mL (1,308), DL3 10,323 ng/mL (2,129); AUC_0-24h DL1 44,492 ng·h/mL (12,904), DL2 76,569 ng·h/mL (25,790), DL3 132,903ng·h/mL (40,482). The mean (SD) accumulation ratio (C1 D15 AUC_0-24h : C1 D1 AUC_0-24h ) was 3.9 (0.7) for DL1, 2.4 (0.3) for DL2, and 1.4 (0.6) for DL3. Pts received a median of 1 C (range (1-21+). Pts with NF1 PN received 1, 4, and 6 C of pexidartinib and had stable disease. One pt with peritoneal mesothelioma is receiving C 21. Conclusions: In children, pexidartinib was tolerated at all dose levels, and the recommended phase II dose (RP2D) is 800 mg/m²/dose once daily. This dose exceeds the adult RP2D of 1000 mg/day. Enrollment on the expansion cohort is ongoing. Clinical trial information: NCT02390752