Phase 0/1 trial of ONC206 - a novel imipridone for children with diffuse midline gliomas and recurrent malignant brain tumors
Phase 0/1 trial of ONC206 - a novel imipridone for children with diffuse midline gliomas and recurrent malignant brain tumors
批准号:
10700080
负责人:
Sabine Mueller
金额:
$58.71万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-07 至 2027-08-31
关键词:
AdultApoptosisBiological AssayBiological MarkersBiological ModelsBiopsyBloodBlood - brain barrier anatomyBrainBrain NeoplasmsCRISPR/Cas technologyCell SurvivalCellsChildChildhoodChildhood Brain NeoplasmClinicalClinical DataCorrelative StudyDataDiagnosisDisease MarkerDopamine D2 ReceptorDoseDrug KineticsEnrollmentFeesFutureGenetic TranscriptionGenomicsH3 K27M mutationHumanIn VitroKnock-outLeadLocationLong-Term SurvivorsMalignant neoplasm of brainMitochondriaMitochondrial DNAMitochondrial ProteinsModelingMolecularNeuroanatomyNewly DiagnosedNewly Diagnosed DiseaseOperative Surgical ProceduresOralOutcomeOutcome MeasureParticipantPatient Outcomes AssessmentsPatientsPenetrancePenetrationPeptide HydrolasesPharmaceutical PreparationsPharmacodynamicsPhasePhase 0/1 Clinical TrialPhase 0/1 TrialPhase I/II Clinical TrialPlayPontine structurePopulationPrognosisProteinsQuality ControlQuality of Life AssessmentRadiationRadiation therapyRecommendationRecurrenceRecurrent diseaseRegional AnatomyRelapseRoleSafetySample SizeSerine ProteaseSerumSurvival RateTNFRSF10B geneTNFSF10 geneTestingThalamic structureTimeToxic effectTumor TissueUp-RegulationVertebral columnarmbiological adaptation to stressblood-brain barrier penetrationblood-brain tumor barriercirculating DNAclinical efficacyclinical predictorscohortdesigndiffuse midline gliomafirst-in-humangenomic datahealth related quality of lifein vivoin vivo Modelirradiationmedulloblastomametabolomicsmisfolded proteinmolecular subtypesmouse modelneuro-oncologynovelnovel therapeuticspatient populationpediatric patientsphase 1 studypotential biomarkerpre-clinicalpredictive markerprotein expressionradiation effectradiological imagingresponseresponse biomarkersafety assessmentsafety testingstandard of caresynergismtargeted agenttranscription factor CHOPtreatment responsetumortumor DNAyoung adult
中文摘要
项目总结
英文摘要
Project Summary
The aim of this phase 0/1 clinical trial is to assess the safety and preliminary efficacy of the novel, orally available,
blood brain barrier (BBB) penetrant imipridone ONC206 in pediatric patients with malignant brain tumors
including diffuse midline gliomas (DMG). We show that ONC206 exerts its activity in DMGs and medulloblastoma
through activation of the mitochondrial protease ClpP, a serine protease that plays a central role in mitochondrial
protein quality control by degrading misfolded proteins. ClpP activation through ONC206 lead to apoptosis
involving upregulation of ATF4 and C/EBP homologous protein (CHOP) and induction of DR5 and TRAIL. In our
preliminary analyses, we have found that ClpP expression correlates with ONC206 response in vitro and that
ONC206’s effect is completely abrogated in H3K27M models with CRISPR/Cas9 knockout. Our in vivo data
demonstrate that ONC206 leads to significant survival benefit in relevant in vivo model systems. Based upon
this exciting preliminary data, this will be the first study to test the safety and to determine the recommended
phase-2 dose (RP2D) of ONC206 as a single agent in pediatric patients including patients with DMGs and other
recurrent malignant brain tumors. Further, we will test ONC206 as single agent and in combination with radiation
in newly diagnosed and with re-irradiation in relapsed pediatric DMGs. We will assess the safety, PK profile and
preliminary efficacy of ONC206 in four different cohorts: (1) in newly diagnosed DMG, (2) in DMG patients who
completed radiation therapy, (3) in DMG patients at time of recurrence with re-irradiation and (4) other recurrent
malignant brain tumors. Using a Bayesian optimal interval (BOIN) design the maximal sample size will be 3-42
per cohort. All cohorts will be expanded so that 12 patients per cohort have been treated at the RP2D. To
investigate the BBB penetration of ONC206, 40 patients will be treated at the RP2D in a phase 0 component of
the study, stratified by anatomic region since penetrance might differ based on tumor location (pontine, thalamic
vs. other locations). Within the confines of a phase 1 study, we will also assess progression fee and overall
survival. For each patient we will collect tumor tissue, CSF and serum for correlative studies with a focus CLpP
expression as a potential biomarker of response. We will also assess tumor circulating DNA as potential marker
for disease for treatment response. Further, we will assess quality of life and patient reported outcomes, which
is critically important but has not yet been done comprehensively in this patient population. This will be the first
study to comprehensively assess ONC206 in this pediatric patient population and will lay the groundwork for
future combination trials.
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