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.

A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study

“…Overall, there was no observed evidence of an impact of everolimus on ribociclib pharmacokinetics. When administered alone, everolimus pharmacokinetic profiles in this pediatric population were comparable with those reported in children and adults 42,48,49 . Median single dose and steady state half-lives for everolimus alone (11.4 to 18.6 hours) agreed with the median values reported in pediatric patients with refractory solid tumors (15.9 to 22.2 hours).…”

“…Median single dose and steady state half-lives for everolimus alone (11.4 to 18.6 hours) agreed with the median values reported in pediatric patients with refractory solid tumors (15.9 to 22.2 hours). 42,48 Steady state exposures of everolimus combined with ribociclib were about 2.5-fold higher than that of everolimus alone. This may suggest an impact of ribociclib on everolimus pharmacokinetics, although results should be interpreted with caution due to the large interpatient variability.…”

Off-Label Medication: From a Simple Concept to Complex Practical Aspects

“…Perhaps the most important aspect regarding the off-label practice, and one of the main advantages, is that it fulfills the unmet medical needs by the conventional therapeutic approaches, increasing the access to medication for special categories of patients. In agreement with the EC report on off-label use, the literature reveals that off-label practice is widespread in rare diseases [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ], oncology [ 12 , 13 , 14 , 15 , 16 ], pediatrics [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ], and psychiatry (especially in pediatric and elderly populations) [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. It is difficult to establish a prevalence or a pattern of general off-label prescribing, since it embraces many forms, and it is divided into many categories.…”

“…As it occurs in common practice, a monoclonal antibody/another agent can be augmented to the standard chemotherapy in an off-label regimen, but the main chemotherapy remains on-label [ 64 , 65 ]. Biological therapies with monoclonal antibodies show a promising pathway in suppressing the cancer response, e.g., rituximab, bevacizumab, lenvatinib [ 14 , 15 , 16 ], but many types of cancer are still unresponsive to monotherapy, requiring combination regimens. Off-label therapy in cancer is, therefore, indispensable and will always be used, to a certain extent, for several reasons: clinical care of multiple tumor types and certain patient’s characteristics are not always covered by the prescribing information in routine practice, there are situations in which the practitioners are willing to try medication with uncertain evidence outside clinical trials for patients with advanced cancer or metastatic stage of the disease, and unawareness of the prescriber of the existence of approved drugs for certain types of cancer [ 62 ].…”

Immunotherapies for Pediatric Solid Tumors: A Targeted Update

“…Bevacizumab (anti-VEGF monoclonal antibody) was studied retrospectively in a pediatric cohort of 18 patients with relapsed/refractory sarcomas in combination with appropriate chemotherapeutic regimens and was shown to be generally well tolerated aside from cytopenias, and appeared to be associated with prolonged disease-free intervals in some patients with widely metastatic disease [45]. Investigators conducted a phase I study looking at the combination of bevacizumab with everolimus, an mTOR inhibitor, in 15 children with recurrent or refractory solid tumors and identified no DLTs and no objective responses [46]. A second phase I study evaluated the combination of bevacizumab, sorafenib, and low-dose cyclophosphamide in 24 children and found grade III/IV toxicities of lymphopenia in 17 patients, hypertension in four patients, hand/foot rash in three patients, and elevated lipase in three patients.…”