A Maintenance Protocol of Sirolimus in Combination With Metronomic Chemotherapy in Children With High-Risk Solid Tumors
Summary
The primary objective of this study is 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.
Detailed description
Sirolimus, also known as rapamycin, is a potent immunosuppressive drug. Due to its profound immunosuppressive actions, sirolimus was initially developed and received regulatory approval for the indication of prevention of allograft rejection following solid organ transplant. Sirolimus also possesses anti-tumor activity through its anti-proliferative effect, by the inhibition of translation of key messenger ribonucleic acids (mRNAs) into proteins required for cell cycle progression from the G1 to the S phase. Palliative care with the use of antiangiogenic metronomic chemotherapy in the form of low-dose daily oral administration of etoposide and cyclophosphamide in combination with antiangiogenic agents such as celecoxib, is feasible and well-tolerated in children with refractory solid tumors Sirolimus is used orally in adults and children for the prevention of allograft rejection following solid organ transplant. The Pediatric Preclinical Testing Program (PPTP) performed testing of sirolimus as a single agent against an in vitro panel of pediatric cell lines, as well as against in vivo pediatric tumor panels. Sirolimus exhibited variable inhibition of cell line growth, ranging from 19% to 85% (median 49%). This study has three cohorts: a prospective cohort of patients with high-risk extracranial solid tumor, a prospective cohort of patients with recurrent solid tumors (any histology) in second complete remission, and a historical control cohort of patients matched on diagnosis, age, metastatic site, and date of diagnosis. The matched historical controls will be obtained from the same treating institution as the corresponding case to account for institutional differences in treatment and supportive care. The primary objective of the study is 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.
Arms & interventions
- DrugSirolimus
Sirolimus is given at a dose of 2 mg/m2 once daily. The amber oral dose syringe should be used to withdraw the prescribed amount of sirolimus oral solution from the bottle. The solution can be drunk or administered at once to assure delivery of all of the medication. It is safe for administration through a nasogastric or G-tube. For tablets, the tablet should not be crushed, split, or otherwise altered. As with the liquid dosing form, the tablets should be given within two hours each day and should be at consistent intervals with regard to meals.
- DrugCyclophosphamide
A synthetic antineoplastic drug chemically related to the nitrogen mustards. The drug is administered orally daily, in the formulation appropriate for age. The solution should be diluted in 20-30 ml of appropriate liquid before administration through nasogastric (NG) tube or gastrostomy (G) tube, with adequate flushing after administration to prevent obstruction of the feeding tube.
- DrugEtoposide
A semisynthetic derivative of podophyllotoxin which functions as mitotic inhibitor but does not interfere with microtubular assembly. The drug is administered orally daily, in the formulation appropriate for age.
- DrugCelecoxib
The drug is administered orally daily, in the formulation appropriate for age.The solution is safe for administration through a nasogastric or G-tube.
Outcome measures
Primary
Two-year progression-free survival in patients with high-risk solid tumors
Two-year progression-free survival in patients with high-risk solid tumors who complete a 12- month course of maintenance chemotherapy with daily sirolimus and twice daily celecoxib on a backbone of low-dose oral metronomic chemotherapy following completion of "standard" therapy as compared to a historical cohort of matched patients treated with observation only following completion of "standard" therapy.
Time frame: up to 2 years
Secondary
Median progression-free survival of children with high-risk solid tumors
Time frame: up to 2 years
Two-year progression-free survival for all prospectively enrolled participants
Time frame: up to 2 years
Two-year overall survival for all prospectively enrolled participants
Time frame: up to 2 years
Number of cases of severe toxicities
Time frame: up to 2 years
Number of patients who come off protocol therapy due to toxicity or non-compliance
Time frame: up to 2 years
Median progression-free survival of children with recurrent solid tumors in second complete remission
Time frame: up to 2 years
Eligibility criteria
Study locations (5)
Aflac Cancer & Blood Disorders Centers
Atlanta, Georgia, 30329
Children's Healthcare of Atlanta
Atlanta, Georgia, 30329
Washington University School of Medicine
St Louis, Missouri, 63110
Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC)
Pittsburgh, Pennsylvania, 15224
Texas Children's Cancer Center
Houston, Texas, 77030