Papers by Kathleen Neville
The Lancet Haematology, 2022
BACKGROUND In high-income countries, standard care for primary stroke prevention in children with... more BACKGROUND In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. METHODS SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935. FINDINGS Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression. INTERPRETATION Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. FUNDING National Institute of Neurological Disorders and Stroke.
Pediatric Neurology, 2021
BACKGROUND Nigeria has the highest proportion of children with sickle cell anemia (SCA) globally;... more BACKGROUND Nigeria has the highest proportion of children with sickle cell anemia (SCA) globally; an estimated 150,000 infants with SCA are born annually. Primary stroke prevention in children with SCA must include Nigeria. We describe capacity-building strategies in conjunction with two National Institutes of Health-funded primary stroke prevention trials (a feasibility trial and phase III randomized controlled trial) with initial hydroxyurea treatment for children with SCA and abnormal transcranial Doppler (TCD) velocities in Nigeria. We anticipated challenges to conducting clinical trials in a low-resource setting with a local team that had not previously been involved in clinical research and sought a sustainable strategy for primary stroke prevention. METHODS This is a descriptive, prospective study of challenges, solutions, and research teams in two trials that enrolled a total of 679 children with SCA. RESULTS As part of the capacity-building component of the trials, over eight years, 23 research personnel (physicians, nurses, research coordinators, a statistician, and a pharmacist) completed a one-month research governance and ethics training program at Vanderbilt University Medical Center, USA. A lead research coordinator for each site completed the Society of Clinical Research Professionals certification. TCD machines were donated; radiologists and nonradiologists were trained and certified to perform TCD. A scalable E-prescription was implemented to track hydroxyurea treatment. We worked with regional government officials to support ongoing TCD-based screening and funding for hydroxyurea for children with SCA at a high risk of stroke. CONCLUSIONS Our trials and capacity building demonstrate a sustainable strategy to initiate and maintain pediatric SCA primary stroke prevention programs in Africa.
Pediatric Hematology and Oncology, 2020
Blood
Introduction: In children with sickle cell anemia (SCA) without transcranial Doppler (TCD) screen... more Introduction: In children with sickle cell anemia (SCA) without transcranial Doppler (TCD) screening, the incidence rates of ischemic strokes is approximately the same among children living in low- and high- low-resource settings (Pediatr Neurol. 2019;95:73-78.) with a prevalence of ~ 11%. However, in high-income settings, the standard use of TCD ultrasonography, coupled initially with monthly blood transfusion therapy has dropped the stroke prevalence to < 1%. In a low-income setting, such as Nigeria, where 50% of children in the world with SCA are born (150,000 per year), initial monthly blood transfusion therapy is not practical for most children. In the Stroke Prevention in Nigeria (SPIN) Feasibility Trial (NCT01801423), fixed moderate-dose hydroxyurea was associated with a decreased rate of strokes in children with SCA and abnormal time-averaged mean of the maximum velocity (TAMMV) TCD measurements (≥200cm/sec) when compared to no treatment in the STOP Trial, 0.76 and 10.7 s...
Journal of Clinical Oncology
10028 Background: Brentuximab vedotin (ADCETRIS) is a novel antibody-drug conjugate that targets ... more 10028 Background: Brentuximab vedotin (ADCETRIS) is a novel antibody-drug conjugate that targets CD30, a cell surface antigen expressed by HL and sALCL. The ph 1 portion of this study evaluated safety, pharmacokinetics (PK), and recommended ph 2 dose (RP2D) of brentuximab vedotin in pediatric pts with RR CD30-expressing tumors. Methods: Ph 1/2, open-label, multicenter study in pts aged 2 to <18 years with RR HL or sALCL (5 to <18 years for HL). Pts received brentuximab vedotin by IV infusion once every 21 days (Q3wk). Ph 1 start dose was 1.4 mg/kg escalated to 1.8 mg/kg in a traditional 3+3 design. Results: 12 pts (median age 14.5 y; 10 HL; 2 sALCL) received brentuximab vedotin in the ph 1 portion (mg/kg/dose [n]: 1.4, [3]; 1.8 [9]). 1.8 mg/kg cohort was expanded from 6 to 9 pts to raise the ph 1 pediatric experience to 12 pts before the ph 2 portion. At data cut, pts had received a median of 3 cycles (range, 1–8). 11 pts (92%) had ≥1 treatment-emergent adverse event (TEAE): 2...
Experimental and Molecular Therapeutics
The Lancet. Haematology, 2018
Despite remarkable progress in the treatment of newly-diagnosed classical Hodgkin's lymphoma ... more Despite remarkable progress in the treatment of newly-diagnosed classical Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, treatment of relapsed or refractory disease remains challenging. The aims of this study were to assess the safety, tolerability, recommended phase 2 dose, and efficacy of brentuximab vedotin in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. This open-label, dose-escalation phase 1/2 study was done at 12 centres across eight countries (France, Germany, Italy, Mexico, The Netherlands, Spain, UK, and USA). We recruited paediatric patients aged 7-18 years with relapsed or refractory classical Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, for whom standard treatment was unavailable or no longer effective. Participants were allocated to receive brentuximab vedotin at 1·4 mg/kg (phase 1) or 1·8 mg/kg (phases 1 and 2) via intravenous infusion once every 3 weeks fo...
Scientific reports, Jan 27, 2018
High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressiv... more High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival t...
PloS one, 2018
Osteosarcoma is an orphan disease for which little improvement in survival has been made since th... more Osteosarcoma is an orphan disease for which little improvement in survival has been made since the late 1980s. New drug discovery for orphan diseases is limited by the cost and time it takes to develop new drugs. Repurposing already approved FDA-drugs can help overcome this limitation. Another limitation of cancer drug discovery is the lack of preclinical models that accurately recapitulate what occurs in humans. For OS using dogs as a model can minimize this limitation as OS in canines develops spontaneously, is locally invasive and metastasizes to the lungs as it does in humans. In our present work we used high-throughput screens to identify drugs from a library of 2,286 FDA-approved drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. The identified lead compound was then tested for synergy with 7 other drugs that have demonstrated activity against OS. These results were confirmed with in vitro assays and an in vivo murine model of OS. ...
Molecular Cancer Therapeutics
British Journal of Clinical Pharmacology
The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbami... more The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HC new) vs. those receiving chronic therapy (HC chronic), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. METHODS Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration vs. time profiles were evaluated with a model independent approach in the HC new and HC chronic groups. Various predictive scenarios were analysed to evaluate whether systemic exposure with hydroxycarbamide could be accurately predicted. RESULTS Absorption of hydroxycarbamide was rapid, variable and dose independent. Dose-normalized peak plasma concentrations and drug exposure (AUC) were higher, and weight-normalized apparent oral clearance was lower in the HC new group. We assessed a PK-guided dosing strategy along with other predictive scenarios and found that inclusion of plasma samples only slightly improved the accuracy of AUC predictions when compared to a population-based method.
The Journal of pharmacy and pharmacology, 2017
Prednisone is a widely used anti-inflammatory for a variety of conditions. While oral liquid form... more Prednisone is a widely used anti-inflammatory for a variety of conditions. While oral liquid formulations of prednisone enable weight-based dosing, children frequently find them to be objectionable due to bitter taste. This limitation of prednisone can adversely impact patient acceptance and may result in non-compliance. Efforts to mask flavours often result in poorly controlled, heterogeneous particle distributions and can provide ineffective taste masking. The present work utilized a novel drug delivery technology developed by Orbis Biosciences, Inc., to create an oral taste-masked formulation of prednisone. The study examined the palatability of Orbis' microsphere prednisone formulation in healthy young adults (n = 24). Four test articles were used in the study including a reference formulation (Roxanne Laboratories), a control and the test formulation (Orbis) prepared in two different ways. Study participants were randomized in a crossover design. Results indicated that the ...
American journal of hematology, Jan 25, 2017
The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence-based ... more The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence-based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non-imaging TCD measurements (≥ 200 cm/s) received moderate fixed-dose hydroxyurea therapy (∼20 mg/kg/day). A comparison group of children with TCD measurements < 200 cm/s was followed prospectively. Approximately 90% (337 of 375) of families agreed to be screened, while 92% (25 of 27) of those with abnormal TCD measurements, on two separate occasions, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85 fL at baseline to 101.3 fL at 24 months, demonstrating adherence to hydroxyurea. The comparison group consisted of 210 children...
Journal of pediatric oncology nursing : official journal of the Association of Pediatric Oncology Nurses, 2017
Neuroblastoma, an embryonic cancer of the sympathetic nervous system, is the most common extracra... more Neuroblastoma, an embryonic cancer of the sympathetic nervous system, is the most common extracranial solid tumor in childhood. Dinutuximab (formerly called ch14.18), a monoclonal antibody targeting the disialoganglioside GD2, has been shown to significantly improve survival rates in patients with high-risk neuroblastoma. However, the safe and effective use of dinutuximab therapy in these high-risk patients requires medical expertise in patient selection, treatment administration, and the monitoring and management of adverse events. Findings of the randomized phase III study (ANBL0032) led to the approval of dinutuximab for the treatment of children with high-risk neuroblastoma. Multi-institutional nursing approaches to implementing standard protocols ensure the effective management of high-risk neuroblastoma patients receiving dinutuximab immunotherapy. Understanding and implementing recommendations for the management of the clinically important and most common adverse events are e...
Pediatric blood & cancer, Jan 10, 2017
A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Admini... more A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m(2) ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectr...
Journal of hematology & oncology, Jan 7, 2017
Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide.... more Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate) in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival. Hence, there is a substantial need for new therapies. The inability to control the metastatic progression of this localized cancer stems from a lack of complete knowledge of the biology of osteosarcoma. Consequently, there has been an aggressive undertaking of scientific investigation of various signaling pathways that could be instrumental in understanding the pathogenesis of osteosarcoma. Here, we review these cancer signaling pathways, ...
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Papers by Kathleen Neville