Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome.
Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.
['Keppler-Noreuil|Kim M|KM|', 'Sapp|Julie C|JC|', 'Lindhurst|Marjorie J|MJ|', 'Darling|Thomas N|TN|', 'Burton-Akright|Jasmine|J|', 'Bagheri|Mohammadhadi|M|', 'Dombi|Eva|E|', 'Gruber|Ashlyn|A|', 'Jarosinski|Paul F|PF|', 'Martin|Staci|S|', 'Nathan|Neera|N|', 'Paul|Scott M|SM|', 'Savage|Ronald E|RE|', 'Wolters|Pamela L|PL|', 'Schwartz|Brian|B|', 'Widemann|Brigitte C|BC|', 'Biesecker|Leslie G|LG|']
D000293:Adolescent D000328:Adult D000631:Aminopyridines D002648:Child D005260:Female D006801:Humans D007093:Imidazoles D008297:Male D020714:Maximum Tolerated Dose D008875:Middle Aged D009506:Nevus D010146:Pain D010766:Phosphorylation D010865:Pilot Projects D011379:Prognosis D016715:Proteus Syndrome D051057:Proto-Oncogene Proteins c-akt D014018:Tissue Distribution D055815:Young Adult
miransertib Proteus syndrome overgrowth mosaicism connective tissue nevus phase I study