A phase 2 study of sirolimus in combination with metronomic chemotherapy (CHOAnome) in children with recurrent and/or refractory solid and CNS tumors.

10054 Background: Outcomes for recurrent and/or refractory (R/R) solid and central nervous system (CNS) tumors remain poor. Sirolimus, an mTOR inhibitor, has both antiproliferative and antiangiogenic effects, and the mTOR pathway is activated in many cancers. Low-dose metronomic chemotherapy also decreases neovascularization and has demonstrated activity in many pediatric tumors. We previously conducted a phase 1 trial establishing the dose (2 mg/m 2 ), safety and tolerability of sirolimus in combination with metronomic chemotherapy. The current study is a prospective, multi-institutional phase 2 trial to determine the objective response rate (ORR) in children with R/R solid and CNS tumors treated with this regimen (NCT02574728); herein we report the results of the solid tumor stratum. Methods: Patients aged 12 months to 30 years with R/R extracranial solid tumors were eligible. Patients were required to have measurable disease and no known curative therapeutic options. Treatment consisted of continuous sirolimus (2 mg/m 2 /dose PO daily), celecoxib (100 mg PO BID), and oral etoposide (50 mg/m 2 /day; max: 100 mg) alternating every 21 days with oral cyclophosphamide (2.5 mg/kg/day; max: 100 mg) in 42-day cycles. Sirolimus was dose-adjusted to maintain a serum trough concentration of 10-15 ng/ml. Response was determined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Enrollment proceeded using a Fleming’s two-stage design based on best overall response (BOR), requiring 2 objective disease status determinations. Results: Twenty-four solid tumor patients were enrolled; 20/24 were evaluable for response. Median age was 14.6 years (range: 2.5–20.5); 9 (45%) were female. Diagnoses included desmoplastic small round cell tumor (DSRCT; n = 3), osteosarcoma (n = 4), Wilms tumor (n = 2), neuroblastoma (n = 5), and one each of Ewing sarcoma, rhabdomyosarcoma, CIC-rearranged sarcoma, clear cell sarcoma-like tumor of the GI tract (CCST), juvenile xanthogranuloma (JXG), and hemangiopericytoma. Median number of cycles was 2 (range: 1-13). Best response after any cycle was partial response (PR) in 2 (CCST and JXG), stable disease (SD) in 8, and progressive disease (PD) in 10 for an objective response rate of 10%. BOR was PR in 2 (10%), SD in 5 (25%), PD in 11 (55%), and unknown in 2 (10%). Median PFS was 3.6 months (range: 1.0-26.2) and median OS was 15.5 months (range: 1.0-55.4). One-year PFS was 26.2% [95% confidence interval (CI): 11.9-57.8%) with 1-year OS of 59.6% (95% CI: 35.1-77.4%). Six patients had ≥SD for ≥6 months [CCST (n = 1), DSRCT (n = 1), JXG (n = 1), hemangiopericytoma (n = 1), and neuroblastoma (n = 2)]. Conclusions: The combination of sirolimus with metronomic chemotherapy showed limited activity in patients with R/R solid tumors, although prolonged disease stabilization was seen across multiple histologies consistent with a metronomic approach. Clinical trial information: NCT02574728 .