Abstracts

Rationale: Seizures that are refractory to both medical and surgical therapy increase the risk of morbidity and mortality in children with epilepsy. At this point in time, options for these children are sparse and suboptimal. This hypothesis-driven phase 1 study aims to evaluate the use of a mammalian target of rapamycin [mTOR] inhibitor, ABI-009, in this subset of challenging participants. The underlying hypotheses being tested in trial are: (1) ABI-009 is a safe and well-tolerated medication in children who have medically-refractory epilepsy and have failed epilepsy surgery, and (2) The addition of ABI-009 therapy to the current clinical standard of continued antiepileptic medications results in improved epilepsy control. This is unique among trials of antiepileptic medications in that it also studies mTOR inhibition in a non- Tuberous Sclerosis Complex (TSC) specific population for whom few additional effective therapies exist. Methods: This is a prospective, single-center, phase 1 safety study to investigate the safety, tolerability, seizure control, and quality of life in participants age 3-26 years with medically-refractory epilepsy who failed epilepsy surgery. These participants have continued seizures despite being at least 3 months post-epilepsy surgery (resective surgery with an intent to cure). Upon enrollment, participants are first continued and observed on their preexisting, clinically prescribed antiepileptic drug (AED) regimen for 1 month. At the 1-month mark, participants receive weekly ABI-009 intravenously at different dose levels in cohorts of 3 participants each using the standard 3+3 dose-finding design. ABI-009 is be continued for a total of 3 weeks. ABI-009 is then be discontinued and the participants are be observed for an additional 3 months. There is intended expansion of the maximum tolerated dose (MTD) cohort to an estimated additional 6 participants for a maximum possible enrollment of 18 participants. Primary objectives are to determine safety and tolerability of ABI-009 in this population. This includes recording dose-limiting toxocity (DLT) and MTD as well as recording all adverse events (AEs). Tolerability refers to the adherence to the prescribed regimen and the number of patients that withdraw from the study after dosing begins. Secondary objectives are to: (1) determine efficacy by recording seizure frequencies, response rate, and frequency of seizure-free days; and (2) to determine quality of life changes using Quality of Life for Children with Epilepsy Parent Form (QOLCE) and Nisonger Child Behavioral Rating Form (NCBRF). Results: At present date there have been a total of 6 patients enrolled and treated on study, with the second cohort coming to completion. The first cohort received ABI-009 5mg/m2 and no significant dose-limiting toxicities were appreciated. At present the second cohort has received ABI-009 10mg/m2 also with no significant dose-limiting toxicities appreciated. No patients have withdrew after receiving study drug, with 100% adherence to prescribed ABI-009 regimen. In the first cohort, the three patients experienced seizure frequencies (seizures per week) before study drug as 1.9, 10.8, and 23.9 compared to 0.0, 15.0, and 6.0 on the last week of study drug, respectively. The three patients experienced seizure-free days before study drug as 21/29, 13/31, and 2/31 compared to 7/7, 2/7, and 5/7 on the last week of study drug, respectively. Conclusions: At present, the preliminary data from the RaSuRE trial suggests that ABI-009 is a safe and well-tolerated medication in the cohort of pediatric patients. There is an early suggestion of efficacy, which will be closely followed in the remaining cohorts and considered as this trial moves into a phase 1b/phase 2. Funding: Funding for this trial was provided by AADI Biosciences.