Sirolimus and Metronomic Chemotherapy for the Treatment of High-Risk Solid Tumors in Children, AflacST1903 Study

Summary

Objectives

PRIMARY OBJECTIVE:
I. To improve the 2-year progression-free survival in children with high-risk solid tumors who are administered a maintenance regimen with continuous sirolimus administered on a backbone of metronomic chemotherapy following the completion of “standard” therapy, as compared to high-risk solid tumor patients treated with observation alone following completion of “standard” therapy.

SECONDARY OBJECTIVES:
I. To compare the median progression-free survival of children with high-risk solid tumors who are administered a maintenance regimen with sirolimus administered orally once daily in combination with metronomic chemotherapy following the completion of “standard” therapy with that of a historical cohort of matched patients treated with observation alone following completion of “standard’ therapy.
II. To determine the progression-free survival in children with high-risk solid tumors who are administered a maintenance regimen with continuous sirolimus administered orally once daily with celecoxib, and oral etoposide alternating every 21 days with oral cyclophosphamide in a 42-day cycle following the completion of “standard” therapy.
III. To determine the overall survival in children with high-risk solid tumors who are administered a maintenance regimen with sirolimus administered orally once daily for 42 days in combination with metronomic chemotherapy following the completion of “standard” therapy.
IV. To determine the incidence of severe toxicities of sirolimus administered in combination with metronomic chemotherapy administered on this schedule in the maintenance setting.
V. To determine the feasibility of completion of a 12-month course of maintenance chemotherapy following completion of “standard” therapy.
VI. To determine the median progression-free survival of children with recurrent solid tumors in second complete remission following completion of an initial relapse treatment regimen.

EXPLORATORY OBJECTIVES:
I. To determine if a patient-specific assay detecting multiple somatic variants can be developed and subsequently utilized to detect circulating tumor deoxyribinucleic acid (DNA) (ctDNA) in the setting of minimal residual disease in pediatric patients with high-risk solid tumors. If ctDNA is detected while on study, changes in detectability and ctDNA levels will be monitored over time in each patient and descriptively correlated with outcome.
II. To describe the tumor molecular profiles of pediatric high-risk solid tumors and correlate the findings with clinical outcome using Clinical Laboratory Improvement Act (CLIA)-certified molecular profiling platforms already in use at participating institutions.

OUTLINE:
Patients receive sirolimus orally (PO) once daily (QD) and celecoxib PO twice daily (BID) on days 1-42, etoposide PO QD on days 1-21, and cyclophosphamide PO QD on days 22-42. Treatment repeats every 42 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days and then yearly thereafter.