A multicenter, phase II trial of maintenance sirolimus in combination with metronomic chemotherapy in children and adolescents with high-risk solid tumors.
Authors: Sutton Kathryn S. , Armstrong Amy E. , Bukowinski Andrew J. , Foster Jennifer , George Bradley A. , Smart Sherri K. , Azer Sally , Ebelhar Jonathan , Martin Melissa A. , Powell Christie , Leong Traci , Richer Edward J. , Yin Hong , Cash Thomas 
Published: June 2023

TPS10072 Background: Risk of relapse for children with high-risk solid tumors (ST) remains unacceptably high despite aggressive multimodal therapy. Maintenance therapy is an emerging option to improve outcomes. Sirolimus, an inhibitor of mammalian target of rapamycin, is a potent immunosuppressant with antiproliferative and antiangiogenic effects. Low-dose metronomic chemotherapy along with the cyclooxygenase-2 inhibitor celecoxib also decreases neovascularization in in vitro and in vivo systems. The maximum tolerated dose (MTD) of sirolimus in combination with celecoxib and etoposide alternating with cyclophosphamide was determined in a phase I study in pediatric patients with relapsed/refractory ST. The regimen was well-tolerated and showed best response of stable disease in 8/18 subjects and partial response in 1/18. The efficacy of this regimen in relapsed/refractory ST is being tested in a Phase II study (NCT02574728). We hypothesize that patients with high-risk ST administered a 12-month course of this maintenance regimen will have improved 2-year progression-free survival (PFS) when compared to matched historical patients who were observed following completion of upfront therapy. Methods: This is a phase II study of sirolimus in combination with celecoxib and alternating low-dose etoposide and cyclophosphamide delivered as maintenance therapy. Sirolimus will be given at the MTD of 2mg/m2/day with celecoxib 100mg twice daily and oral etoposide 50mg/m2/day (max 100mg) alternating every 21 days with oral cyclophosphamide 2.5mg/kg/day (max 100mg). This study includes: 1) a prospective cohort of patients with high-risk ST in first complete remission (CR), 2) a prospective cohort of patients with recurrent ST in second CR, and 3) a historical cohort matched 2:1 with cohort 1 on diagnosis, age, metastatic sites, and date of diagnosis treated with observation following upfront therapy. The study will enroll up to 38 patients in cohort 1. Eligible subjects are children (1-30 years) with a diagnosis of high-risk extracranial ST (metastatic sarcoma, desmoplastic small round cell tumor, malignant rhabdoid tumor) in first CR or any ST in second CR. Patients enrolled in upfront clinical trials are excluded. Primary endpoint is 2-year PFS of cohort 1 compared to the historical cohort. Secondary endpoints are median PFS of cohort 1, 2-year PFS and overall survival of cohorts 1 and 2, incidence of severe toxicities, and feasibility of completing the 12-month course following standard upfront therapy. Exploratory objectives include evaluation of circulating tumor DNA (ctDNA) in this population of patients in CR or with minimal disease burden and correlation of clinically obtained tumor molecular profiling with outcomes. As of January 2023, 12 subjects are enrolled, 9 in cohort 1 and 3 in cohort 2. Clinical trial information: NCT04469530 .