Clinical Efficacy Evaluation of First-in-class Imipridone ONC201 in Recurrent Type II Endometrial Cancer

Project Summary ONCis a selective antagonist of the G protein coupled receptorGPCRdopamine receptor domainDRDthat is overexpressed in endometrial cancerECdue to its pindependent control of the Akt ERK signaling pathwaysONCis a first in class small molecule exhibits anticancer efficacy in a wide range of refractory cancersincluding pmutant cellsby simultaneously inactivating Akt and ERK signalingresulting in cell cycle arrest and apoptosisType II EC comprises non endometrioid histologyi eserousclear cell and mucinousthat are generally associated with more aggressive clinical behaviorThis proposal supports a clinical trial of ONCin Type II EC patients with recurrent diseasewho have mutations in pas well as deregulated Akt and ERK pathways in their tumorsIn clinical trialsONChas been exceptional well toleratedpossessed a therapeutic pharmacokinetic profileand exhibited sustained pharmacodynamics and anti cancer activity in advanced cancer patientsNo andgtGradedrug related adverse events were observed in the first in human trialdespite achieving therapeutic blood levels and demonstrating signs of biological activityOf theevaluable patients in that trialthere wereadvanced endometrial cancer patients and several exhibited clinical benefit and all expressed DRDin their archival tumor specimensAmong these heavily pretreatedpatientsthe median number of prior treatments waspatients had prior radiation and all patients had prior surgeryAfterdoses of ONCone patient with clear cell EC had a mixed response with andgtdecrease in lymphadenopathyTwo EC patients experienced prolonged stable disease lasting forandweeksincluding ayear old patient with serouspapillary EC who also had a significant and sustained reduction in the size of a metastatic lung lesionThusEC emerged as the most promising tumor type from a preliminary efficacy perspective in this first in human trial in advanced solid tumorsBased on the clinical responses observed in this patient populationin this fast track application we propose to first evaluate a pilot cohort of patients to evaluate the preliminary single agent efficacy profile in Type II EC patientsDepending on these clinical resultswe will then conduct a larger study enrolling an additionalpatients to determine the efficacy of ONCeither as a single agent or in combination with paclitaxelPhase AimEvaluation of preliminary single agent efficacy profile in Type II EC patientsPhase AimDetermine the efficacy of ONCin Type II ECThis proposal seeks to provide a safe and durable treatment for patients with a disease that has few treatment options and a dismal prognosis Project Narrative This proposal seeks to develop a new cancer drug called ONCwhich has a new way of killing cancer cells that no longer respond to other treatmentsfor patients who have Type II endometrial cancerIn a previous first in human advanced solid tumor studypatients with this type of cancer had their tumors shrink and target of this new drug was expressed in their tumorsThese patients have very poor prognoses and limited treatment optionswith no new drugs approved by the FDA in almostyears for this disease and therefore ONCrepresents an important treatment option for these patients