A phase 2 study of sirolimus in combination with metronomic chemotherapy (CHOAnome) in children with recurrent and/or refractory solid and CNS tumors.
Authors: Cash Thomas , Aguilera Dolly , Ginn Kevin Fate , Hoffman Lindsey M. , Keesari Rohali , Petersen William C. , Caywood Emi H. , Qayed Muna , Connelly Erin , Milla Sarah S. , Castellino Robert C. , Fangusaro Jason , MacDonald Tobey J. , Wetmore Cynthia , Katzenstein Howard 
Published: June 2023

10024 Background: Multiple low-dose, anti-angiogenic (metronomic) chemotherapy regimens have demonstrated activity in pediatric solid and central nervous system (CNS) tumors. The mTOR pathway is activated in many human cancers and provides an attractive therapeutic target. We previously conducted a phase 1 trial establishing the dose (2 mg/m2), safety and tolerability of sirolimus in combination with metronomic chemotherapy. In the current study, we conducted a prospective, multi-institutional phase 2 trial to determine the objective response rate (ORR) in pediatric patients with recurrent and/or refractory (R/R) solid and CNS tumors treated with this regimen (NCT02574728); herein we report the results of the CNS tumor stratum. Methods: Patients aged 12 months to 30 years with R/R CNS tumors of all world health organization (WHO) grades were eligible. After completion of the trial’s first stage, patients with diffuse intrinsic pontine glioma (DIPG) were excluded due to lack of efficacy. Patients were required to have measurable disease and no known curative therapeutic options. Treatment consisted of continuous sirolimus (2 mg/m2/dose PO daily), celecoxib (100 mg PO BID), and oral etoposide (50 mg/m2/day; max dose: 100 mg) alternating every 21 days with oral cyclophosphamide (2.5 mg/kg/day; max dose: 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 a modified Response Assessment in Neuro-Oncology (RANO) criteria. Enrollment proceeded using a Fleming’s two-stage design based on best overall response (BOR), which required two objective disease status determinations. Results: Twenty-two CNS tumor patients were enrolled; 20/22 were evaluable for response. Median age was 11.2 years (range: 5.9 – 18.1); 6 (30%) were female. Diagnoses included DIPG (N = 5), medulloblastoma (N = 3), high-grade (HG) glioma (N = 5), HG/malignant neuroepithelial tumor (N = 3) and one each of diffuse midline glioma, atypical teratoid/rhabdoid tumor (ATRT), choroid plexus carcinoma, and pineoblastoma. Median number of cycles was 2 (range: 1-6). Best response after any cycle was partial response (PR) in 4 [medulloblastoma (N = 3); pineoblastoma (N = 1)], stable disease (SD) in 4, and progressive disease (PD) in 12 for an ORR of 20%; all patients with DIPG had PD at or before their first disease evaluation. BOR was PR in 3 (15%), SD in 2 (10%), PD in 14 (70%), and unknown in 1 (5%). Four patients had SD or response for ≥ 6 months [medulloblastoma (n = 1), pineoblastoma (N = 1), and HG glioma (N = 2)]. Conclusions: The combination of sirolimus with metronomic chemotherapy showed activity in pediatric patients with some R/R CNS tumors, producing objective responses in medulloblastoma and pineoblastoma. Patients with DIPG did not benefit from this regimen and should be offered alternative treatments. Clinical trial information: NCT02574728 .