Phase 1 study of ABI-009 (nab-rapamycin) for surgically refractory epilepsy (RaSuRE)
Koko Hall
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Search for more papers by this authorRussell Saneto
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorStephanie Randle
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorMark S. Wainwright
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorPatricia Berry
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorSarah Leary
Cancer and Blood Disorders Center, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorGhayda Mirzaa
Department of Genetic Medicine, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorJason Lockrow
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorHannah Goldstein
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorJeffrey Ojemann
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorRosita Thiessen
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorHope Willis
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorErin Sullivan
Biostats, Epidemiology, and Analytics in Research Core, Seattle Children's Hospital, Seattle, Washington, USA
Search for more papers by this authorRenee Rivers
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorJani Klein
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorCorresponding Author
Jason S. Hauptman
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Division of Neurosurgery, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA
Correspondence
Jason Hauptman, Division of Neurosurgery, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA.
Email: [email protected]
Search for more papers by this authorKoko Hall
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Search for more papers by this authorRussell Saneto
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorStephanie Randle
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorMark S. Wainwright
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorPatricia Berry
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorSarah Leary
Cancer and Blood Disorders Center, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorGhayda Mirzaa
Department of Genetic Medicine, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorJason Lockrow
Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorHannah Goldstein
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorJeffrey Ojemann
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorRosita Thiessen
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorHope Willis
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorErin Sullivan
Biostats, Epidemiology, and Analytics in Research Core, Seattle Children's Hospital, Seattle, Washington, USA
Search for more papers by this authorRenee Rivers
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorJani Klein
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Search for more papers by this authorCorresponding Author
Jason S. Hauptman
Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
Division of Neurosurgery, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA
Correspondence
Jason Hauptman, Division of Neurosurgery, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA.
Email: [email protected]
Search for more papers by this authorClinical trial registration: This study was registered with clinicaltrials.gov NCT03646240 and sponsored by Seattle Children's Hospital.
Abstract
Objective
Seizures that are refractory to medical and surgical therapy increase the risk of morbidity and mortality in children with epilepsy. Novel therapeutic trials for this population remain sparse and suboptimal. This Phase 1 study evaluates the (1) safety, tolerability, and (2) preliminary efficacy of ABI-009 (nab-rapamycin) in children with medically and surgically refractory epilepsy.
Methods
Children with medically intractable epilepsy and a history of resective surgery who experienced >8 seizures during the 30-day baseline were included. Participants maintained their existing antiseizure medication regimens throughout the study. ABI-009 was administered over 3 weeks using a 3 + 3 dose-escalation design, with dosing cohorts of 5, 10, and 20 mg/m2. Treatment was then discontinued, and participants were observed for a 90-day follow-up period. Data were collected on seizure frequency, seizure type, adverse events, medical and laboratory assessments, the Quality of Life in Childhood Epilepsy (QOLCE), and the Nisonger Child Behavior Rating Form (NCBRF).
Results
Twelve participants received ABI-009 and completed all study visits. Seizure etiologies included tuberous sclerosis complex, focal cortical dysplasia, and hemimegalencephaly, although Mammalian target of rapamycin involvement was not required for inclusion. No doses were missed, and dose escalation progressed through all levels. The maximum tolerated dose was 20 mg/m2. All 12 participants experienced at least one treatment-emergent adverse event (TEAE), with the majority being mild (80%). No participants withdrew from the study voluntarily or by necessity secondary to TEAEs, and there were no serious adverse events. The median change in the weekly seizure rate was a 37.6% reduction from baseline to treatment completion. The treatment response rate (≥25% seizure reduction) was 66.7%, and two participants achieved seizure freedom by follow-up.
Significance
ABI-009 was deemed safe and tolerable in a pediatric cohort with medically and surgically refractory epilepsy, establishing a maximum tolerated dose of 20 mg/m2 and showing early signs of efficacy.
CONFLICT OF INTEREST STATEMENT
Dr. Jason Hauptman is a consultant for Medtronic. The remaining authors have no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
All requests for data will be reviewed by the Intellectual Property Core at Seattle Children's ([email protected]) to identify if the request is subject to any intellectual property of confidentiality obligations.
Supporting Information
| Filename | Description |
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| epi18555-sup-0001-DataS1.docxWord 2007 document , 31.6 KB |
Appendix S1. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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