A Phase I trial combining fenretinide and safingol to target overproduction of di
结合芬维A胺和 safingol 的 I 期试验,旨在解决 di 的过量生产
基本信息
- 批准号:8291974
- 负责人:
- 金额:$ 31.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultBehaviorBiochemicalBiochemistryBiological AssayBiological AvailabilityBloodBolus InfusionCalibrationCancer cell lineCanis familiarisCellsCeramidesCisplatinClinicalClinical TrialsClinical Trials DesignContinuous InfusionCoupledDataDoctor of PhilosophyDoseDrug CombinationsDrug ExposureDrug FormulationsDrug KineticsEmulsionsErythroFenretinideFutureGrantHematopoieticHumanIn SituIn VitroIn complete remissionInfusion proceduresIntravenousLaboratoriesLifeLymphomaMalignant Childhood NeoplasmMalignant NeoplasmsMammalian CellMaximum Tolerated DoseMeasurementMeasuresModelingMononuclearOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPhasePhase I Clinical TrialsPlasmaPropertyReactive Oxygen SpeciesRelapseRetinoidsSafingolScheduleSignal TransductionSolid NeoplasmSphingolipidsSurrogate MarkersT-Cell LymphomaToxic effectToxicologyVariantbaseburden of illnesscancer cellcancer therapycytotoxiccytotoxicitydihydroceramideimprovedkinase inhibitorleukemia/lymphomamanneoplastic cellnoveloncologyphase 1 studypre-clinicalprogramsresponsesphinganinesphingosine 1-phosphatesphingosine kinasetumor
项目摘要
DESCRIPTION (provided by applicant): A Phase I trial combining intravenous fenretinide and safingol to target overproduction of cytotoxic dihydroceramides in malignant cells PI: Barry J. Maurer, MD PhD ABSTRACT Fenretinide (4-HPR) is a p53-independent retinoid selectively cytotoxic to cancer cells via increase of reactive oxygen species and the de novo increase of native long chain D-erythro-dihydroceramides. Safingol is L-threo- dihydrosphingosine, an artificial stereochemical variant of sphinganine, the native precursor of dihydroceramides in mammalian cells. We have shown in human and canine cancer cell lines that safingol is incorporated into long-lived, L-threo-dihydroceramides. Our preclinical data demonstrated that safingol strikingly synergized fenretinide cytotoxicity in vitro by simultaneously increasing both artificial L-threo-dihydroceramides and native D-erythro-dihydroceramides in a tumor cell-specific manner. We hypothesized that this novel, cancer-specific biochemistry might be achievable in human cancers should adequate drug levels be achievable in patient tumors in situ. Via an NCI RAID grant, we prepared novel intravenous emulsion formulations of both fenretinide and safingol suitable for high-dose delivery. Our phase I adult trials of intravenous 4-HPR demonstrated that it is well-tolerated, achieved high circulating plasma 4-HPR levels, and produced durable complete responses in T-cell lymphomas with additional signals of activity in solid tumors. A Phase I trial of our intravenous safingol formulation demonstrated that it was well-tolerated in combination with cisplatin at safingol doses believed sufficient to attain the desired dihydroceramide modulation. Our IND-directed, canine toxicology studies showed that the combination of intravenous safingol and fenretinide was well-tolerated and lacked hematopoietic toxicity within our target dosing. We now propose to conduct a phase I trial of intravenous safingol in combination with intravenous 4-HPR in adult solid tumors and lymphomas. The proposed trial will define the maximally tolerated dose (MTD) of intravenous safingol when combined with fenretinide, the pharmacokinetics of both agents in combination, obtain ancillary markers of the pharmacodynamic actions of both agents in combination by measuring plasma sphingolipid and sphingosine-1-phosphate levels, and, within the confines of a phase I trial, determine the activity of this novel drug combination. This trial is the first in man to specifically target the dihydroceramide pathway as a cytotoxic cancer treatment. If successful, this novel biochemical attack on malignant cells will constitute a broad-based, p53-independent therapy widely active in both adult and pediatric malignancies.
描述(由申请人提供):一项联合静脉注射芬维A胺和沙芬戈以靶向恶性细胞中细胞毒性二氢神经酰胺过度产生的I期试验PI:巴里J. Maurer,MD PhD摘要芬维A胺(4-HPR)是一种p53非依赖性类维生素A,通过增加活性氧和从头增加天然长链D-β-二氢神经酰胺,对癌细胞具有选择性细胞毒性。Safingol是L-苏型-二氢鞘氨醇,是鞘氨醇的人工立体化学变体,鞘氨醇是哺乳动物细胞中二氢神经酰胺的天然前体。我们已经在人类和犬癌细胞系中表明,沙芬戈被掺入长寿命的L-苏型-二氢神经酰胺中。我们的临床前数据表明,沙芬戈显着协同芬维A胺的体外细胞毒性,同时增加人工L-苏型-二氢神经酰胺和天然D-邻-二氢神经酰胺在肿瘤细胞特异性的方式。我们假设,这种新的,癌症特异性的生物化学可能在人类癌症中实现,如果在原位患者肿瘤中可以达到足够的药物水平。通过NCI RAID资助,我们制备了适合高剂量递送的芬维A胺和沙芬戈的新型静脉内乳剂制剂。我们的静脉注射4-HPR的I期成人试验证明,它是耐受性良好的,达到了高循环血浆4-HPR水平,并在T细胞淋巴瘤中产生持久的完全反应,在实体瘤中具有额外的活性信号。我们的静脉注射沙芬戈制剂的I期试验表明,在沙芬戈剂量下,它与顺铂联合使用时耐受性良好,据信足以达到所需的二氢神经酰胺调节作用。我们的IND指导的犬毒理学研究表明,静脉内沙芬戈和芬维A胺的组合耐受性良好,并且在我们的目标剂量范围内没有造血毒性。我们现在建议在成人实体瘤和淋巴瘤中进行静脉注射沙芬戈联合静脉注射4-HPR的I期试验。拟定的试验将确定静脉注射沙芬戈与芬维A胺联合给药时的最大耐受剂量(MTD),两种药物联合给药的药代动力学,通过测量血浆鞘脂和1-磷酸鞘氨醇水平获得两种药物联合给药的药效学作用的辅助标志物,并在I期试验范围内确定这种新型药物联合给药的活性。这项试验是第一个在人体中特异性靶向二氢神经酰胺途径作为细胞毒性癌症治疗的试验。如果成功的话,这种对恶性细胞的新型生化攻击将构成一种广泛基础的,p53非依赖性的治疗方法,在成人和儿童恶性肿瘤中广泛有效。
项目成果
期刊论文数量(0)
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CHARLES Patrick REYNOLDS其他文献
CHARLES Patrick REYNOLDS的其他文献
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{{ truncateString('CHARLES Patrick REYNOLDS', 18)}}的其他基金
Targeting Shared Vulnerabilities in Alternate Telomere Lengthening (ALT) Cancers
针对替代端粒延长 (ALT) 癌症的共同弱点
- 批准号:
10390601 - 财政年份:2022
- 资助金额:
$ 31.17万 - 项目类别:
Targeting Shared Vulnerabilities in Alternate Telomere Lengthening (ALT) Cancers
针对替代端粒延长 (ALT) 癌症的共同弱点
- 批准号:
10543855 - 财政年份:2022
- 资助金额:
$ 31.17万 - 项目类别:
Robust assays to define telomere maintenance mechanisms as cancer biomarkers.
将端粒维持机制定义为癌症生物标志物的稳健测定。
- 批准号:
10300210 - 财政年份:2021
- 资助金额:
$ 31.17万 - 项目类别:
Robust assays to define telomere maintenance mechanisms as cancer biomarkers.
将端粒维持机制定义为癌症生物标志物的稳健测定。
- 批准号:
10693944 - 财政年份:2021
- 资助金额:
$ 31.17万 - 项目类别:
Alternate telomere maintenance mechanisms in high-risk neuroblastoma as prognostic indicators and therapeutic targets
高危神经母细胞瘤的替代端粒维持机制作为预后指标和治疗靶点
- 批准号:
10225312 - 财政年份:2018
- 资助金额:
$ 31.17万 - 项目类别:
Alternate Telomere Maintenance Mechanisms in High Risk Neuroblastoma as Prognostic Indicators and Therapeutic Targets Yr 1 to 5
高风险神经母细胞瘤中的替代端粒维持机制作为第 1 至 5 年的预后指标和治疗目标
- 批准号:
10366253 - 财政年份:2018
- 资助金额:
$ 31.17万 - 项目类别:
Alternate telomere maintenance mechanisms in high-risk neuroblastoma as prognostic indicators and therapeutic targets
高危神经母细胞瘤的替代端粒维持机制作为预后指标和治疗靶点
- 批准号:
10472494 - 财政年份:2018
- 资助金额:
$ 31.17万 - 项目类别:
A Phase I trial combining fenretinide and safingol to target overproduction of di
结合芬维A胺和 safingol 的 I 期试验,旨在解决 di 的过量生产
- 批准号:
8188810 - 财政年份:2011
- 资助金额:
$ 31.17万 - 项目类别:
Xenograft models of human neuroblastoma bone metastases.
人神经母细胞瘤骨转移的异种移植模型。
- 批准号:
6687132 - 财政年份:2003
- 资助金额:
$ 31.17万 - 项目类别:
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