A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors

Abstract

Background/purpose To determine the maximum tolerated dose, toxicities, and response of sirolimus combined with oral metronomic therapy in pediatric patients with recurrent and refractory solid and brain tumors. Procedure Patients younger than 30 years of age with recurrent, refractory, or high‐risk solid and brain tumors were eligible. Patients received six‐week cycles of sirolimus with twice daily celecoxib, and alternating etoposide and cyclophosphamide every three weeks, with Bayesian dose escalation over four dose levels (NCT01331135). Results Eighteen patients were enrolled: four on dose level (DL) 1, four on DL2, eight on DL3, and two on DL4. Diagnoses included solid tumors (Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma) and brain tumors (glioblastoma multiforme [GBM], diffuse intrinsic pontine glioma, high‐grade glioma [HGG], medulloblastoma, ependymoma, anaplastic astrocytoma, low‐grade infiltrative astrocytoma, primitive neuroectodermal tumor, nongerminomatous germ cell tumor]. One dose‐limiting toxicity (DLT; grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain and grade 3 mucositis) on DL3, and two DLTs (grade 3 dehydration and grade 3 mucositis) on DL4. The recommended phase II dose of sirolimus was 2 mg/m2 (DL3). Best response was stable disease (SD) in eight patients, and partial response (PR) in one patient with GBM. A patient with HGG was removed from the study with SD and developed PR without further therapy. Western blot analysis showed inhibition of phospho‐S6 kinase in all patients during the first cycle of therapy. Conclusion The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing.

Systematic review of phase‐I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research

“…A total of 146 clinical trials were included in further analysis. Trial descriptions were extracted from registry websites, 53 publications, 8‐63 and 9 abstracts (ASCO website n = 6; results section of websites n = 3).…”

Metronomic Chemotherapy

“…Two different areas of research can be identified: mCHT as maintenance treatment in different pediatric cancer [ 109 ] Metronomic combination of different chemotherapy drugs [ 110 , 111 ] mCHT in combination with other drugs [ 112 , 113 , 114 ] …”

“…Qayed et al [ 112 ] explored the role of sirolimus in a Phase 1 trial in combination with celecoxib BID, and alternating etoposide and CTX administered every 3 weeks in 18 patients younger than 30 years of age with recurrent, refractory, or high-risk solid and brain tumors. The study established the recommended dose for sirolimus at 2 mg/m 2 .…”

Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma

“…Besides, multiple pathways and genes associated with metabolic and environmental stress have been recovered, suggesting that autophagy modulation might be a new strategy to fight glioblastoma. Several autophagy inhibitors and its derivates have been extensively studied in vitro in several groups of glioblastoma patients [190,191]. Although testing them in vitro using various glioblastoma cells clearly shows the benefits for anticancer therapy, the precise mechanism of their therapy remains unclear.…”