Summary Brain tumors are the most common solid tumor diagnosed in childhood that account for significant morbidity and mortality. New therapies are urgently needed; hence, we conducted the first ever prospective open-label phase II trials of the biological response modifier, poly-ICLC, in children with brain tumors. Poly-ICLC is a synthetic double-stranded RNA that has direct antiviral, antineoplastic, and immune adjuvant effects. A total of 47 children representing a variety of brain tumor histopathologic subtypes were treated with poly-ICLC. On the basis of the results of the initial phase II trial, an expanded prospective phase II trial in low-grade glioma (LGG) has been initiated. MRI was used to acquire volume-based measures of tumor response. No dose-limiting toxicities have been observed. In the initial study 3 of 12 subjects with progressive high-grade gliomas (HGGs) responded, and 2 of 4 children with progressive LGG experienced stable disease for 18 to 24 months. In the follow-up LGG phase II study, 2 of 5 LGG patients were stable over 18 months, with 1 stable for 6 months. Overall 5 of 10 LGG patients have responded. On the basis of low toxicity and the promising LGG response, poly-ICLC may be effective for childhood LGG, and the results justify biomarker studies for personalization of poly-ICLC as a single agent or adjuvant.
Embryonal tumor with multilayered rosettes (ETMR) are rare pediatric brain tumors with increased malignant potential. Despite the advances in multimodal treatment schemes the overall 5-year event free survival rates for ETMR are not favorable. Further, therapeutic regimes are limited to a case by case basis due to the limited amount of literature and guidelines available for treating childhood ETMR. We report one patient with refractory ETMR who was successfully treated by implementing a molecular profiling approach which identified the tyrosine kinase inhibitor dasatinib as a viable therapy. Our results suggest that utilizing this precision medicine approach might prove useful in treating patients with refractory ETMR.
Background: Venous thromboembolism (VTE) is an important clinical concern in children with or without cancer. Experience with dalteparin, a low molecular weight heparin, in the treatment of VTE in adults with cancer has been extensively published, but data in children are limited. Aims: We sought to determine the twice-daily dalteparin dose required to achieve target Anti-Xa levels of 0.5-1.0 IU/mL, as well as its pharmacodynamics (PD), effi cacy, and safety in the treatment of VTE in children <19 years old, with or without cancer. Methods: This prospective, multi-center, Phase 2, open-label study consisted of 3 phases: 1) Dose Adjustment Phase of up to 7 days, in which Anti-Xa levels were measured following the fi rst, second or third dose of dalteparin, until achievement of the target level; 2) PD Phase of up to 7 days, to obtain 2 randomized PD plasma samples for Anti-Xa determination; and 3) Follow-Up Phase, to complete up to 90 days of anticoagulant therapy. Patients were assessed for symptomatic new or progressive (i.e., recurrent) VTE as well as clinically relevant bleeding during treatment. Surveillance VTE imaging was performed at 90 ± 14 days. Results: The safety population consisted of 38 patients who received at least 1 dose of dalteparin (<2 years: n = 3; ≥2 to <8 years: n = 8; ≥8 to <12 years, n = 7; ≥12 to <19 years: n = 20). Twenty-six patients (68%) had a diagnosis of cancer at baseline, of which 23 (88%) were haematological malignancies. The median [range] dalteparin dose required to achieve target Anti-Xa levels decreased with age (<2 years: 207.5 IU/kg [201.5-213.5 IU/kg]; ≥2 to <8 years: 128.15 IU/ kg [123.9-180.3 IU/kg]; ≥8 to <12 years: 125 IU/kg [124.5-152.6 IU/kg]; ≥12 to <19 years: 116.7 IU/kg [99.1-159 IU/kg]) (Figure).Therapeutic Anti-Xa levels were achieved in 90% of patients within a mean (SD) of 2.6 days (1.54 days); the mean (SD) number of dose adjustments per patient was 0.7 (0.98). One patient (3%) developed symptomatic recurrent VTE. No patients reported clinically-relevant bleeding. Four patients (11%) had treatment-related serious adverse events. 62% of patients had complete resolution of their VTE at the end of the 90-day reporting period. Summary/Conclusion:Twice-daily dalteparin dosing achieved therapeutic levels in 90% of children with or without cancer, with a satisfactory tolerability profi le. The median therapeutic doses of dalteparin were higher for the two youngest age cohort groups (<2 years and 2 to <8 years). NCT00952380 Sources of Research Support: This study was sponsored by Pfi zer Ltd.
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