Phase II Trial of Irinotecan and Temozolomide in Combination With Existing High-Dose Alkylator–Based Chemotherapy for Treatment of Patients With Newly Diagnosed Ewing Sarcoma

PURPOSE Irinotecan and temozolomide (iT) have antitumor activity in relapsed Ewing sarcoma (ES). The purpose of this phase II trial was to evaluate whether iT added to an alkylator-intensified five-drug regimen (Ewing Family of Tumors [EFT]) improved the 4-year event free survival (EFS) for patients with newly diagnosed localized ES. METHODS Patients with localized ES received six cycles of iT consolidation following completion of 21 weeks of EFT chemotherapy; patients with metastatic disease received 10 intercalated cycles of iT during EFT. The primary end point was 4-year EFS for patients with localized disease, with 85% and 70% of patients without events deemed promising and not promising, respectively. Secondary end points included EFS for metastatic patients, overall survival (OS), toxicity, and exploratory circulating tumor DNA analyses. RESULTS Eighty-three patients were enrolled (46 localized, 37 metastatic; median age 16 years). The 4-year EFS for patients with localized disease was 76% (95% CI, 64% to 90%), which did not exceed the predefined threshold for unpromising efficacy. Among patients with metastatic disease, 4-year EFS was 56% (95% CI, 37% to 84%) for those with lung-only metastases and 43% (95% CI, 25% to 74%) for those with extrapulmonary metastases. Febrile neutropenia occurred in 96% of patients, most frequently following alkylator-containing cycles. Secondary malignancies developed in four patients. No unexpected toxicities were observed. CONCLUSION The addition of iT to high-dose, alkylator-based up-front chemotherapy did not exceed the historical EFS benchmark in patients with radiographically localized ES.