Bevacizumab In Children Research Articles

Intravitreal bevacizumab in choroidal neovascularisation in Vogt‐Koyanagi‐Harada disease in a child: A review of literature

Aims/Purpose: Interest of bevacizumab in children in the treatment of choroidal neoplasms in Vogt Koyanagi Harada syndrome.Methods: In this work we report the case of an extra‐foveal choroidal neovascularization in a child followed for VKH syndrome with a good response to intravitreal injections of bevacizumab.Results: We report the case of a 12‐year‐old child who initially presented to the hospital in 2020 for bilateral decreased visual acuity and headache. There was no history of systemic disease. Initial visual acuity was 1/10 in both eyes. Biomicroscopic examination revealed granulomatous retrodescemetic precipitates, 2× anterior chamber tyndall, 1× vitreous tyndall, and bilateral exudative retinal detachment associated with bilateral papilledema in both eyes. Based on these findings, a diagnosis of Vogt‐Koyanagi‐Harada syndrome was made, and treatment was initiated with intravenous, oral, and topical corticosteroids. Visual acuity improved to 6/10 OD and 7/10 OS the following month. The patient was then followed up at the university hospital regularly. After controlling the inflammation, steroids were decreased over a period of 2 years but the patient relapsed at high dose to declare cortico‐dependence. Anti‐TNF alpha was started to control the inflammation and visual acuity remained stable until July 2022. Choroidal neovascularization then developed, reducing the patient's visual acuity to 3/10 in both eyes within 1 month. Fluorescein angiography and macular OCT confirmed the diagnosis of extrafoveolar choroidal neovascularization in both eyes. After obtaining informed consent, intravitreal bevacizumab was injected 3 times at 6 week intervals in each eye. After the 6th injection, the patient's best‐corrected visual acuity improved to 8/10 in the right eye and 10/10 in the left eye. The fundus photograph illustrates the regression of the choroidal neovessels. Fluorescein angiography confirmed the reduction in leakage. Choroidal neovascular membranes can cause severe visual impairment and are a major challenge in the management of patients.Conclusions: This case illustrates that intravitreal bevacizumab has a possible role in the treatment of the disease, with regression of neovascular lesions in the eye.

Preliminary report of a multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: An NF Clinical Trials Consortium study.

2056Background: Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with...

Multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: an NF Clinical Trials Consortium study (S23.004)

Multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: an NF Clinical Trials Consortium study (S23.004)

Pharmacokinetics of Bevacizumab in Three Patients Under the Age of 3 Years with CNS Malignancies

BackgroundBevacizumab is a recombinant antibody that is increasingly used in pediatric malignancies. The pharmacokinetics of bevacizumab in pediatric patients have been shown to be influenced by tumor localization and body weight. In this report, we present data on the pharmacokinetics and safety of bevacizumab in children under the age of 3 years with central nervous system (CNS) malignancies.MethodsThree patients (mean age 22 months) were treated with intravenous bevacizumab 10 mg/kg every 2 weeks. In total, 20 trough and peak bevacizumab concentrations of 10 treatment cycles were obtained at steady state.ResultsBevacizumab was generally well-tolerated in this age group. The mean trough concentration was 127 ± 29 µg/ml (range 77–155), and the mean peak concentration was 149 ± 13 µg/ml (range 113–157). Trough and peak levels were stable upon repeated treatment cycles in the same patient. In contrast, we determined strong interindividual variations in trough levels. Whereas the plasma concentration of the oldest patient matched the prediction of a previously published model, younger patients showed markedly higher trough levels.ConclusionsSerum peak concentrations of bevacizumab in children under the age of 3 years with CNS malignancies are in a similar magnitude to that found in older children and adults. Thus, a dosing schedule of bevacizumab 10 mg/kg every 2 weeks can be considered sufficient and safe, even in very young children. We further show that very young children with CNS malignancies show a markedly reduced plasma clearance, possibly related to lower body weight or differences in clearance mechanisms of antibodies.

18F-FDOPA PET/MRI for monitoring early response to bevacizumab in children with recurrent brain tumors

Noninvasively predicting early response to therapy in recurrent pediatric brain tumors provides a challenge. 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA) PET/MRI has not been previously studied as a tool to evaluate early response to antiangiogenic therapy in children. The purpose of this study was to evaluate the safety and feasibility of using 18F-FDOPA PET/MRI to assess response to bevacizumab in children with relapsed brain tumors. Six patients with recurrent gliomas (5 low-grade, 1 high-grade) planned to undergo treatment with bevacizumab were enrolled. 18F-FDOPA PET/MRI scans were obtained prior to and 4 weeks following the start of treatment, and these were compared with the clinical response determined at the 3-month MRI. The primary PET measure was metabolic tumor volume (MTV) at 10 to 15 min after 18F-FDOPA injection. For each tumor, the MTV was determined by manually defining initial tumor volumes of interest (VOI) and then applying a 1.5-fold threshold relative to the mean standardized uptake value (SUV) of a VOI in the frontal lobe contralateral to the tumor. 18F-FDOPA PET/MRI was well tolerated by all patients. All tumors were well visualized with 18F-FDOPA on the initial study, with peak tumor uptake occurring approximately 10 min after injection. Maximum and mean SUVs as well as tumor-to-brain ratios were not predictors of response at 3 months. Changes in MTVs after therapy ranged from 23% to 98% (n = 5). There is a trend towards the percent MTV change seen on the 4-week scan correlating with progression-free survival. 18F-FDOPA PET/MRI was well tolerated in pediatric patients and merits further investigation as an early predictor of response to therapy.

Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P < 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P < 0.05). A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications.

Add-on-therapy with bevacizumab in children and adolescents with poor prognosis non-CNS solid tumors

Bevacizumab is increasingly being used in adult patients with cancer and children with central nervous system (CNS) tumors. Little, however, is known about the efficacy, risks, and benefits of bevacizumab administration in non-CNS tumors of childhood. The aim of the present study was to report on bevacizumab administered as add-on-therapy for poor prognosis non-CNS solid tumors of childhood and adolescence, including a prospective evaluation of side effects of bevacizumab. Seven patients (female: n = 5; median age, 14.5 years) with relapsed (n = 4) or primary metastatic (n = 3) solid non-CNS tumors received bevacizumab at 5-10 mg/kg body weight intravenously every 2-3 weeks. Assessment of cardiac function, thyroid hormone levels, urine analysis, and radiographic responses were carried out every 3 months. The median time of bevacizumab treatment was 10 (range, 5-17) months. Patients received a median of 16 (range, 10-38) bevacizumab infusions. With a median follow-up of 25 (range, 13-38) months, five patients relapsed after 7-25 months and three of them died. Two patients are still in complete remission for 31 and 32 months, respectively. Fraction shortening decreased in two patients. Bevacizumab was associated with new-onset increase in basal thyroid-stimulating hormone (n = 3), mild proteinuria/hematuria (n = 5), intermittent hypertension (n = 2), hypertension requiring antihypertensive medication (n = 3), and epistaxis (n = 2). In two patients, therapy with bevacizumab was terminated because of side effects. Selected patients with relapsed or primary metastatic solid non-CNS tumors of childhood and adolescence might benefit from add-on-therapy with bevacizumab. Although the side effects were usually mild, cardiac monitoring seems to be essential during and after the administration of bevacizumab.

Feasibility and tolerability of bevacizumab in children with primary CNS tumors

Bevacizumab, an antibody to the vascular endothelial growth factor, has demonstrated anti-cancer activity in a number of solid tumors. Fear of intratumoral hemorrhage, however, has slowed its introduction into the treatment of central nervous system (CNS) tumors. Currently, only a small number of children with gliomas received bevacizumab. We retrospectively analyzed 30 patients who received bevacizumab between January 2007 and August 2009. The median age at start of bevacizumab treatment was 9.9 years (range: 1.5-18). Most patients had recurrent/progressive disease, 25 high-grade and 5 low-grade tumors. The median dose of bevacizumab was 9.5 mg/kg (range 5-15 mg/kg) every 2-3 weeks. In total, 478 courses were administered (median/patient 15.9, range: 2-52). The median duration of bevacizumab treatment was 10.0 months (range: 1.6-30.4). Twenty-nine of 30 patients received additional therapy concomitant to bevacizumab. No bevacizumab related intratumoral hemorrhage occurred in any of our 30 patients. Grade III hypertension was seen in two patients. One patient developed nephrotic syndrome requiring cessation of treatment. Grade III and I proteinuria were observed in one and five patients, respectively. New onset lymphopenia occurred in 12/30 and new onset hypothyroidism in 7/30 patients. Impaired wound healing was manageable. No immediate bevacizumab-related cardiotoxicity was observed as evidenced by echocardiography. Bevacizumab appears to be safe for children with primary CNS tumors. Adverse effects did occur but were manageable. No treatment-related death occurred. Long-term monitoring is advisable to detect lymphopenia and hypothyroidism. Hypertension occurred less frequently than in adult patients. Further prospective studies including more patients are warranted.

Phase I Trial and Pharmacokinetic Study of Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study

We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)-neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer. BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors. Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data. BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.

A phase I study of bevacizumab in children with refractory solid tumors: A Children’s Oncology Group study

9017 Background: Bevacizumab is a humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF-A) that has demonstrated significant growth inhibition in several pre-clinical models of pediatric solid tumors. However, the agent has never been tested in pediatric patients. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the dose limiting toxicities (DLTs), and to determine the pharmacokinetics (PK) and recommended phase II dose of bevacizumab administered by IV infusion every 2 weeks in 28-day cycles. Cohorts were enrolled at dose levels of 5, 10, and 15 mg/kg; the final dose level was expanded to include at least 3 children &lt;6 years of age. Serial blood samples were collected for PK, plasma VEGF concentration, and circulating mature and progenitor endothelial cells (CECs/CEPs). Results: 20 patients (10 male), median age 13 yrs (range 1–21), were enrolled at dose levels 5 (n=3), 10 (n=3), and 15 (n=14) mg/kg. 18 patients were fully evaluable for toxicity (one withdrew consent prior to treatment and the second was removed for rapid disease progression). A total of 67 cycles were administered with a median of 3 per patient (range 1–16). Treatment was well tolerated and no DLTs were observed. Only one grade 3 toxicity, lymphopenia, was attributed to drug. Non-dose limiting, grade 1–2 toxicities included infusional reaction (n=3), rash (n=3), mucositis (n=2), and proteinuria (n=3). There was no hypertension, hemorrhage or thrombosis reported. There were no partial or complete responses; 3 pts with Ewings and 2 pts with soft tissue sarcoma had disease stabilization for &gt; 3 months. The serum exposure to bevacizumab as measured by AUC appeared to increase in proportion to dose. The median clearance of bevacizumab was 4.1 ml/day/kg (range 3.2–15.9), and the median T1/2 was 11.8 days (range 3.9–14.6). In some patients, a rapid rate of rise in plasma VEGF, increase in mature CECs or decrease in CEPs was observed. Conclusion: Bevacizumab at doses up to 15mg/kg every two weeks is well tolerated in children with solid tumors. No significant financial relationships to disclose.