A Phase 1 Trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in Advanced NSCLC Patients
MLN0128 (sapanisertib) 和 CB-839 HCl (telaglenastat) 在晚期 NSCLC 患者中的 1 期试验
基本信息
- 批准号:10478111
- 负责人:
- 金额:$ 59.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-31 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:18F-GlutamineAffectAgeBinding SitesBiologyBiopsyBloodCancer PatientCellsCitric Acid CycleClinical DataContractsDataDependenceDiseaseDoseDrug KineticsExhibitsEyeFRAP1 geneGenerationsGenotypeGlucoseGlutaminaseGlutamineGlycolysisGlycolysis InhibitionHistologicHistologyImageImmune checkpoint inhibitorInstitutionInterventionKRAS2 geneKnowledgeLeadLungLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMetabolicMetabolismMetastatic Squamous Cell CarcinomaMethodsModelingMutateMutationNon-Small-Cell Lung CarcinomaOralPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhasePhase I Clinical TrialsPlasmaPlatinumPopulation ControlPositron-Emission TomographyPrognosisProteinsPublishingRecurrenceResistanceSafetyScheduleSignal TransductionSquamous Cell Lung CarcinomaStressTestingTherapeuticTimeTreatment EfficacyTumor Suppressor GenesUnited StatesUp-RegulationUrsidae FamilyWorkXenobioticsbasecheckpoint inhibitionchemotherapycohortcombinatorialdruggable targeteffective therapyefficacy testingfluorodeoxyglucoseglucose metabolisminhibitormolecular subtypesmutantnew therapeutic targetnovelnovel strategiespartial responsepatient prognosispharmacodynamic biomarkerphase I trialphase II trialpre-clinicalresistance mechanismresponsetargeted treatmenttherapy resistanttranscription factortreatment responsetumortumor metabolism
项目摘要
Project Summary/Abstract
Patients with metastatic squamous cell carcinomas of the lung (LUSC) and driver-negative non-small cell lung
cancers (NSCLC) continue to have poor prognoses despite modest gains in survival in the age of immune
checkpoint inhibitors. This is, in large part, due to the absence of targeted therapies for these patients,
treatments which have had the biggest impact on patient prognoses in the past 15 years. The current proposal
focuses on a novel interaction that occurs between a newly characterized NSCLC genotype and its effects on
tumor metabolism. NFE2L2, which encodes for a transcription factor (NRF2) that protects cells from oxidative
and xenobiotic stress and which upregulates TORC1 signaling, is recurrently mutated in 20% of LUSC tumors.
These mutations occur in only a single hotspot domain (Neh2) that serves as the binding site for its negative
regulator, KEAP1, which itself is mutated in 20% of LUSC cases. This pathway is also altered in 30% of KRAS-
mutant lung cancer cases and is associated with poor prognosis and immune checkpoint inhibitor resistance.
Our preliminary pre-clinical and clinical data show that inhibition of TORC1/2 by the orally available drug
TAK228 has anti-tumor efficacy in these contexts, but that a metabolic switch away from glycolysis (blunted by
TORC1/2 inhibition) to glutamine metabolism causes treatment resistance. We show that dual inhibition of
glycolysis (TAK228) and glutaminolysis (CB-839) in mutation-specific LUSC and KRAS-mutant lung contexts
yields synergistic anti-tumor activity. The proposed phase 1 clinical trial is based on the hypothesis that
concurrent inhibition of these pathways with TAK228 and CB-839 will be an effective therapy for subsets of
NSCLC patients who harbor these alterations or have activation of NRF2 signaling. Our phase 1 trial of
TAK228 + CB-839 has three aims, including 1) determination of the recommended expansion dose of TAK228
+ CB-839 in patients with advanced NSCLC; 2) establishing the preliminary efficacy of TAK228 + CB-839 in
pre-selected genotype/histology cohorts; and 3) characterizing the metabolic pharmacodynamic markers in the
blood, tumor, and through imaging. This trial is a first step in what we purport will be a new targeted therapy
option for patients with NSCLC. The next step and longer term objective is to utilize these data as justification
and hypothesis generation for formal phase 2 efficacy testing in a much larger cohort of patients, with an eye
towards executing a study in larger cooperative groups such as LungMAP S1900, which would be uniquely
suited to exploring this combination approach across institutions in the United States.
项目总结/文摘
项目成果
期刊论文数量(0)
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Paul K Paik其他文献
Paul K Paik的其他文献
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{{ truncateString('Paul K Paik', 18)}}的其他基金
A Phase 1 Trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in Advanced NSCLC Patients
MLN0128 (sapanisertib) 和 CB-839 HCl (telaglenastat) 在晚期 NSCLC 患者中的 1 期试验
- 批准号:
10297989 - 财政年份:2021
- 资助金额:
$ 59.14万 - 项目类别:
A Phase 1 Trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in Advanced NSCLC Patients
MLN0128 (sapanisertib) 和 CB-839 HCl (telaglenastat) 在晚期 NSCLC 患者中的 1 期试验
- 批准号:
10673018 - 财政年份:2021
- 资助金额:
$ 59.14万 - 项目类别:
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