Background: Sarcomas express pro-angiogenic factors that may represent therapeutic targets. Pazopanib, an oral multi-kinase inhibitor of VEGFR-(1-3), c-kit, and PDGFR, is FDA-approved for the treatment of advanced soft tissue sarcomas. In a phase 1 study of single-agent pazopanib in children with recurrent or refractory solid tumors, this agent was well tolerated and the clinical activity was encouraging in this heavily pre-treated population. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and cytotoxic chemotherapy. The combination of irinotecan and temozolomide is well tolerated and provides a modest degree of antitumor activity in heavily pre-treated sarcoma patients, thus making it a useful platform onto which new compounds may be tested. Methods: This is a phase 1, open-label, multicenter trial of pazopanib in combination with irinotecan and temozolomide (PAZIT) in children and young adults ages 6-30 years with relapsed or refractory sarcomas (NCT03139331). The primary objectives are to determine the recommended phase 2 dose, describe toxicities, and describe pharmacokinetic parameters in this population. Secondary and exploratory objectives include evaluation of disease response and exploration of pharmacodynamic effects of PAZIT. Pazopanib is administered orally on days 1-21 of 21-day cycles according to assigned dose level. All patients receive fixed doses of irinotecan IV (50 mg/m²/day) or PO (90 mg/m²/day) and temozolomide 100 mg/m²/day PO on days 1-5. Oral cephalosporin diarrhea prophylaxis is required. Dose escalation follows a standard 3+3 design evaluating up to three pazopanib dose levels. Following dose escalation, up to 10 additional patients will be enrolled to the dose expansion cohort to obtain additional toxicity and efficacy data. Correlative studies include changes in plasma angiogenic factors and circulating tumor DNA. Enrollment began in May 2017 and is ongoing. Clinical trial information: NCT03139331