PARC:a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults

Background: The survival for many children with relapsed/refractory cancers remains poor despite advances in therapies. Arginine metabolism plays a key role in the pathophysiology of a number of pediatric cancers. We report the first in child study of a recombinant human arginase, BCT-100, in children with relapsed/refractory hematological, solid or CNS cancers.Procedure: PARC was a single arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the safety profile and the complete depletion of arginine (defined as adequate arginine depletion; AAD <8μM arginine in the blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of patients with pediatric cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with patients continuing to receive treatment until disease progression or unacceptable toxicity.Results: 49 children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II Dose of 1600U/kg iv weekly in children, matching that of adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory patients experienced prolonged radiological SD.Conclusion: Arginine depletion is a clinically safe and achievable strategy in children with cancer. The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population.Clinical trial registration: EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140

Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance.

BACKGROUND: Babies differ from older children with regard to their exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, data describing the effect of SARS-CoV-2 in this group are scarce, and guidance is variable. We aimed to describe the incidence, characteristics, transmission, and outcomes of SARS-CoV-2 infection in neonates who received inpatient hospital care in the UK. METHODS: We carried out a prospective UK population-based cohort study of babies with confirmed SARS-CoV-2 infection in the first 28 days of life who received inpatient care between March 1 and April 30, 2020. Infected babies were identified through active national surveillance via the British Paediatric Surveillance Unit, with linkage to national testing, paediatric intensive care audit, and obstetric surveillance data. Outcomes included incidence (per 10 000 livebirths) of confirmed SARS-CoV-2 infection and severe disease, proportions of babies with suspected vertically and nosocomially acquired infection, and clinical outcomes. FINDINGS: We identified 66 babies with confirmed SARS-CoV-2 infection (incidence 5·6 [95% CI 4·3-7·1] per 10 000 livebirths), of whom 28 (42%) had severe neonatal SARS-CoV-2 infection (incidence 2·4 [1·6-3·4] per 10 000 livebirths). 16 (24%) of these babies were born preterm. 36 (55%) babies were from white ethnic groups (SARS-CoV-2 infection incidence 4·6 [3·2-6·4] per 10 000 livebirths), 14 (21%) were from Asian ethnic groups (15·2 [8·3-25·5] per 10 000 livebirths), eight (12%) were from Black ethnic groups (18·0 [7·8-35·5] per 10 000 livebirths), and seven (11%) were from mixed or other ethnic groups (5·6 [2·2-11·5] per 10 000 livebirths). 17 (26%) babies with confirmed infection were born to mothers with known perinatal SARS-CoV-2 infection, two (3%) were considered to have possible vertically acquired infection (SARS-CoV-2-positive sample within 12 h of birth where the mother was also positive). Eight (12%) babies had suspected nosocomially acquired infection. As of July 28, 2020, 58 (88%) babies had been discharged home, seven (11%) were still admitted, and one (2%) had died of a cause unrelated to SARS-CoV-2 infection. INTERPRETATION: Neonatal SARS-CoV-2 infection is uncommon in babies admitted to hospital. Infection with neonatal admission following birth to a mother with perinatal SARS-CoV-2 infection was unlikely, and possible vertical transmission rare, supporting international guidance to avoid separation of mother and baby. The high proportion of babies from Black, Asian, or minority ethnic groups requires investigation. FUNDING: UK National Institute for Health Research Policy Research Programme

Anticoagulation therapy in children

Thromboembolic disease (TED) is increasingly recognized as a major cause of morbidity and mortality in tertiary pediatrics. Children younger than 1 year of age and teenage girls are at greatest risk of thromboembolism. Although anticoagulation therapy is the treatment of choice for TED, the treatment strategy is often difficult, especially in children. Treatment relies largely on anticoagulation with heparin and warfarin. Recommendations for antithrombotic therapy in children have been loosely extrapolated from recommendations for adults; however, it is likely that optimal treatment of children with TED differs from adults because of important ontogenic features of hemostasis that affect both the pathophysiology of the thrombotic processes and the response to antithrombotic agents. Until recently, the primary treatment for TED has been unfractionated heparin (UFH) in conjunction with warfarin. Warfarin, the most commonly used oral anticoagulant, acts through inhibition of the vitamin K-dependent transcarboxylation reactions that convert precursors of clotting factors into their active form. Appropriate use of UFH and warfarin requires close patient monitoring and dosage adjustments to ensure tolerability and efficacy. In recent years, low molecular weight heparins (LMWH) have become available as alternatives to UFH and warfarin, for both the prevention and treatment of TED. Potentially, LMWH have significant advantages. They have superior pharmacokinetics, which results in minimal laboratory monitoring, offering important benefits to children with poor venous access. Based on available data, LMWHs are at least as effective and well tolerated as UFH, and are more convenient. Although LMWHs are more expensive than UFH, the expense is likely to be offset by savings from a reduced hospital stay

Vandetanib tumor shrinkage in metastatic medullary thyroid cancer allowing surgical resection of the primary site: A case report

Vandetanib has been shown to improve progression-free survival in adults with advanced medullary thyroid cancer. This article describes a pediatric patient with metastatic medullary thyroid cancer secondary to sporadic multiple endocrine neoplasia 2B, treated with vandetanib. At presentation, he had an inoperable primary tumor, with carotid encasement, and pulmonary metastases. Vandetanib induced a significant response: calcitonin and carcinoembryonic antigen levels both fell considerably, primary tumor maximal diameter decreased by 68%, and pulmonary metastases became no longer detectable. This allowed surgical resection of the primary tumor. The patient remains well after over 6 years of vandetanib therapy, with no treatment toxicity

Use of vandetanib in metastatic medullary carcinoma of thyroid in a pediatric patient with multiple endocrine neoplasia 2B

We describe a child with advanced, metastatic, inoperable medullary carcinoma of thyroid associated with multiple endocrine neoplasia 2B and rearranged during transfection mutation with a positive response to vandetanib treatment. He responded well with a fall in calcitonin levels and a reduction in size of the thyroid malignancy, lymph nodes, and pulmonary metastases. He has been on vandetanib for 4 years with good clinical and biochemical response. Vandetanib has a role in the treatment of patients including children with inoperable locally advanced and metastatic medullary carcinoma of thyroid. More information is needed on its use in children and long-term outcome

Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study

none19noneJózsef Zsiros;Laurence Brugieres;Penelope Brock;Derek Roebuck;Rudolf Maibach;Arthur Zimmermann;Margaret Childs;Daniele Pariente;Veronique Laithier;Jean-Bernard Otte;Sophie Branchereau;Daniel Aronson;Arun Rangaswami;Milind Ronghe;Michela Casanova;Michael Sullivan;Bruce Morland;Piotr Czauderna;Giorgio PerilongoJózsef, Zsiros; Laurence, Brugieres; Penelope, Brock; Derek, Roebuck; Rudolf, Maibach; Arthur, Zimmermann; Margaret, Childs; Daniele, Pariente; Veronique, Laithier; Jean Bernard, Otte; Sophie, Branchereau; Daniel, Aronson; Arun, Rangaswami; Milind, Ronghe; Michela, Casanova; Michael, Sullivan; Bruce, Morland; Piotr, Czauderna; Perilongo, Giorgi

Open-label, multicentre, randomised, phase II study of the EpSSG and the ITCC evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients with metastatic soft tissue sarcoma (the BERNIE study)

Purpose We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). Patients and methods Eligible patients aged 656 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo + five cycles of IVA, \ub1bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, \ub1bevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee. Results One hundred and fifty-four patients were randomised to receive chemotherapy alone (n = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8\u201335.9) with chemotherapy and 20.6 months (95% CI: 15.2\u201324.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] = 0.93; 95% CI: 0.61\u20131.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73\u20132.09) versus 0.64 (95% CI: 0.32\u20131.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2\u201347.9) with chemotherapy and 54.0% (95% CI: 40.9\u201366.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6\u201335.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab. Conclusion The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement