A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors

Abstract

Background: The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors.

Methods: In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients.

Results: Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline.

Conclusions: The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4-week cycle for children with recurrent solid tumors.

Keywords: bevacizumab; clinical oncology; everolimus; pediatrics.

Conflict of interest statement

Conflict of interest disclosure: None

© 2020 American Cancer Society.

Figures

Figure 1.

Heat map of P values for pairwise differences in P-4EBP1 Thr/37/46 levels between study time points and overall test P value. P = .049 for overall difference. P = .045 for baseline vs day 27.

Figure 2.

Heat map of P values for pairwise differences in P-AKT Ser473 levels between study time points and overall test P value. P = .071 for overall difference. P = .038 for baseline vs day 14.

Figure 3.

Immunoblot analysis of total AKT (A and C) and P-AKT (B and D) in PBMCs for 2 patients at baseline and days 14 and 27 post treatment.

Figure 4.

Everolimus whole-blood concentration-time profiles after single dose (A) and at steady-state (B). Dots represent individual concentration-time data; crosses are data below the lower limit of quantification. Squares represent 24-hour time points after dose administration on day 2 of course 1 or 2 (excluded from modeling analysis). Solid lines depict mean model predictions.