A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome

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  • Siddharth Srivastava
    Department of Neurology , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Booil Jo
    Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305 , USA
  • Bo Zhang
    Department of Neurology , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Thomas Frazier
    Department of Psychology , John Carroll University, , OH 44118 , USA
  • Anne Snow Gallagher
    Department of Pediatrics , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Fleming Peck
    Department of Neurology , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • April R Levin
    Department of Neurology , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Sangeeta Mondal
    Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305 , USA
  • Zetan Li
    Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305 , USA
  • Rajna Filip-Dhima
    Rosamund Stone Zander Translational Neuroscience Center , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Gregory Geisel
    Rosamund Stone Zander Translational Neuroscience Center , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Kira A Dies
    Rosamund Stone Zander Translational Neuroscience Center , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Amelia Diplock
    Department of Neurology , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Charis Eng
    Genomic Medicine Institute, Cleveland Clinic , Cleveland, OH 44195 , USA
  • Rabi Hanna
    Department of Pediatrics, Hematology, Oncology, Blood and Marrow Transplantation, Cleveland Clinic , Cleveland, OH 44195 , USA
  • Mustafa Sahin
    Department of Neurology , Boston Children’s Hospital, , Boston, MA 02115 , USA
  • Antonio Hardan
    Department of Psychiatry and Behavioral Sciences, Stanford University , Stanford, CA 94305 , USA
  • Julian A Martinez-Agosto

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<jats:title>Abstract</jats:title> <jats:p>PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mechanistic target of rapamycin (mTOR) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism. We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5 mg/m2) in individuals (5–45 years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners’ Continuous Performance Test hit reaction time and Purdue Pegboard Test score. Forty-six participants underwent 1:1 randomization: n = 24 (everolimus) and n = 22 (placebo). Gastrointestinal adverse events were more common in the everolimus group (P &lt; 0.001). Changes in the primary endpoint between groups from baseline to Month 6 were not apparent (Cohen’s d = −0.10, P = 0.518). However, several measures were associated with modest effect sizes (≥0.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior and global improvement. There was a significant difference in EEG central alpha power (P = 0.049) and central beta power (P = 0.039) 6 months after everolimus treatment. Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6 months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I.</jats:p>

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