Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial

Weiss AR, Chen YL, Scharschmidt TJ, Chi YY, Tian J, Black JO, Davis JL, Fanburg-Smith JC, Zambrano E, Anderson J, Arens R, Binitie O, Choy E, Davis JW, Hayes-Jordan A, Kao SC, Kayton ML, Kessel S, Lim R, Meyer WH, Million L, Okuno SH, Ostrenga A, Parisi MT, Pryma DA, Randall RL, Rosen MA, Schlapkohl M, Shulkin BL, Smith EA, Sorger JI, Terezakis S, Hawkins DS, Spunt SL, Wang D. Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2020 Aug;21(8):1110-1122. doi: 10.1016/S1470-2045(20)30325-9. Epub 2020 Jul 20. PubMed PMID: 32702309; PubMed Central PMCID: PMC7745646.

Outcomes for children and adults with advanced soft tissue sarcoma (STS) remain poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiation would improve pathological near complete response rate compared to chemoradiation alone. In this jointly conducted Children’s Oncology Group and NRG Oncology multicentre, randomised, phase 2 trial, we enrolled eligible adults (≥18 years) and children (<18 years) from 57 hospitals within the United States and Canada with unresected, newly diagnosed trunk/extremity STS (> 5 cm, intermediate- or high-grade) of chemotherapy-sensitive histology (synovial sarcoma, angiosarcoma, adult fibrosarcoma, mesenchymal chondrosarcoma, leiomyosarcoma, liposarcoma (excluding myxoid liposarcoma), undifferentiated pleomorphic sarcoma, undifferentiated embryonal sarcoma of the liver, and unclassified STS too undifferentiated to be placed in a specific pathologic category (“soft tissue sarcoma NOS”) using WHO 2013 criteria) and Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 70. Patients received ifosfamide (2.5 g/m2 per dose intravenously on days 1-3 with MESNA) and doxorubicin (37.5 mg/m2 per dose intravenously on days 1-2) + 45 Gy preoperative radiotherapy, followed by surgical resection at Week 13. Allocation concealment was achieved using a web-based system with patients randomly assigned (1:1) in an unblinded fashion to receive or not receive oral pazopanib (< 18 years: 350 mg/m2 once daily; ≥ 18 years: 600 mg once daily) with pazopanib held around delayed surgery. The study projected 100 randomized patients to show an improvement in the rate of ≥ 90% pathologic response by central pathology review at week 13 from 40% to 60%, the primary endpoint. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867.