A Phase I trial combining IV fenretinide and IV safingol to target overproduction

I 期试验结合 IV 芬维A胺和 IV safingol 以解决生产过剩问题

• 批准号: 8646688
• 负责人: William Jay Simpson
• 金额: $ 19.06万
• 依托单位: CERRX, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646688
• 关键词: Address; Adult; Animals; Antineoplastic Agents; Behavior; Biochemical; Biochemistry; Biological Assay; Blood; Bolus Infusion; Calibration; Cancer cell line; Canis familiaris; Cells; Ceramides; Childhood; Cisplatin; Clinical; Clinical Trials; Clinical Trials Design; Continuous Infusion; Cytotoxic Chemotherapy; Data; Dose; Dose-Limiting; Drug Combinations; Drug Exposure; Drug Formulations; Drug Kinetics; Emulsions; Erythro; Fenretinide; Funding; Future; Grant; Health Sciences; Hematopoietic; Human; In Situ; In Vitro; In complete remission; Individual; Infusion procedures; Intravenous; Laboratories; Legal patent; Licensing; Life; Lymphoma; Malignant Childhood Neoplasm; Malignant Neoplasms; Mammalian Cell; Maximum Tolerated Dose; Measures; Modeling; Mononuclear; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Plasma; Property; Reactive Oxygen Species; Relapse; Retinoids; Rights; Safingol; Signal Transduction; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipids; Staging; Surrogate Markers; T-Cell Lymphoma; Testing; Texas; Toxic effect; Toxicology; Universities; Variant; base; burden of illness; cancer cell; cancer therapy; cost; cytotoxic; cytotoxicity; data exchange; design; dihydroceramide; drug development; improved; leukemia/lymphoma; man; neoplastic cell; novel; oncology; phase 1 study; pre-clinical; public health relevance; sphinganine; sphingosine 1-phosphate; tumor

PROJECT SUMMARY/ABSTRACT CerRx, Inc., Lubbock TX, a clinical stage anticancer drug development start-up company, requests critical funding via this SBIR Fast-Track Phase I/II application to support a highly novel, adult Phase I clinical trial of intravenous fenretinide + safingol, for which it licenses both formulation and drug combination IP rights. This trial will be subcontracted to the academic West Texas-based, South Plains Oncology Consortium (SPOC), based at the Texas Tech University Health Sciences Center (TTUHSC). 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, novel intravenous emulsion formulations of both fenretinide and safingol suitable for high-dose delivery were developed. Phase I adult trials of intravenous 4-HPR demonstrated that it is well-tolerated, achieved high circulating plasma 4-HPR levels, and produced multiple durable complete responses in relapsed 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 predicted sufficient to attain the desired dihydroceramide modulation. Our IND-directed, canine toxicology studies showed that the combination of intravenous safingol + fenretinide was well-tolerated and lacked hematopoietic toxicity within our target dosing. Under SBIR Phase I, initial proof-of-concept clinical combination dosing will be conducted. Under SBIR Phase II, a Phase I dose escalation trial of intravenous 4- HPR + safingol in adult solid tumors and lymphomas will be conducted. The Phase I 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 biochemistry may constitute a broad-based, p53-independent therapy widely active in both adult and pediatric malignancies.

项目总结/摘要 CerRx，Inc.，拉伯克德克萨斯州，一家临床阶段的抗癌药物开发初创公司，要求关键的 通过这项SBIR快速通道I/II期申请提供资金，以支持一项高度新颖的成人I期临床试验， 静脉注射芬维A胺+沙芬戈，其许可制剂和药物组合的知识产权。这 试验将分包给位于德克萨斯州西部的学术机构南平原肿瘤学联盟（SPOC）， 德克萨斯理工大学健康科学中心（TTUHSC）芬维A胺（4-HPR）是一种p53- 非依赖性维甲酸通过增加活性氧对癌细胞的选择性细胞毒性， 天然长链D-β-二氢神经酰胺的重新增加。Safingol是L-苏型-二氢鞘氨醇， 神经鞘氨醇的人工立体化学变体，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的癌细胞系中表明，沙芬戈被掺入到长寿命的L-苏型- 二氢神经酰胺我们的临床前数据表明，沙芬戈显着协同芬维A胺的细胞毒性， 在体外，通过同时增加人工L-苏型-二氢神经酰胺和天然D-苏型-二氢神经酰胺， 二氢神经酰胺以肿瘤细胞特异性的方式。我们假设这种新颖的癌症特异性 如果在患者体内达到足够的药物水平， 原位肿瘤通过NCI RAID资助，芬维A胺和沙芬戈的新型静脉乳剂制剂 适合于高剂量递送。静脉注射4-HPR的I期成人试验表明， 耐受性良好，达到了高循环血浆4-HPR水平，并产生了多个持久的完整 复发性T细胞淋巴瘤中的反应与实体瘤中的额外活性信号。的I期试验 我们的静脉注射沙芬戈制剂证明， 预测沙芬戈剂量足以获得所需的二氢神经酰胺调节。我们的IND指导，犬 毒理学研究表明静脉内沙芬戈+芬维A胺的组合耐受性良好， 在我们的目标剂量范围内没有造血毒性。在SBIR第一阶段，初步概念验证临床 将进行联合给药。根据SBIR II期，静脉注射4-羟色胺的I期剂量递增试验， 将在成人实体瘤和淋巴瘤中进行HPR +沙芬戈。I期试验将定义 最大耐受剂量（MTD）的静脉沙芬戈与芬维A胺联合使用时，药代动力学 获得两种药物联合使用时药效学作用的辅助标志物， 通过测量血浆鞘脂和鞘氨醇-1-磷酸水平，以及在 第一阶段试验，确定这种新型药物组合的活性。这项试验是第一次在人体上 靶向二氢神经酰胺途径作为细胞毒性癌症治疗。如果成功，这种新的生物化学可能 构成了一个广泛的基础，p53非依赖性治疗广泛活跃在成人和儿童恶性肿瘤。