Phase I trial of PHP with high-dose IL-2

PHP 联合高剂量 IL-2 的 I 期试验

• 批准号: 6980307
• 负责人: WOLFRAM E. SAMLOWSKI
• 金额: $ 24.61万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-17 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6980307
• 关键词: biomarker; blood chemistry; blood pressure; capillary; cardiovascular disorder; chemical conjugate; clinical research; clinical trial phase I; combination cancer therapy; hemodynamics; hemoglobin; human subject; human therapy evaluation; hypotension; interleukin 2; kidney neoplasms; melanoma; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neuropsychological tests; nitric oxide; patient oriented research; pharmacokinetics; pulmonary artery; statistics /biometry; vascular resistance

DESCRIPTION (provided by applicant): High-dose IL-2 produces complete remissions in a small percentage (5-10%) of patients with metastatic renal carcinoma or melanoma. It is intriguing that many of the IL-2 induced complete remissions have proven durable, with up to 18-year follow-up. The clinical use of IL-2 is limited by severe side effects, particularly hypotension and "vascular leak syndrome"(VLS). Patients treated with high-dose IL-2 require hospitalization for close monitoring and administration of fluids, colloids and pressor medications to treat low blood pressure that occurs in a dose dependent manner. A substantial fraction (1/3 to 1/2) of planned IL-2 doses is usually omitted due to cardiovascular toxicity, which may compromise effectiveness. Our laboratory and clinical studies have shown that synthesis of nitric oxide (NO) is strongly induced following IL-2 treatment. NO is an important mediator of hypotension and vascular leak. We have recently identified a promising new agent, PHP, a pyridoxalated hemoglobin polyoxyethylene conjugate, that appears to be safe in humans and has the potential to prevent both IL-2 induced hypotension and VLS due to its ability to catabolize NO, as well as other potentially injurious oxidative radicals. This grant application is designed to support a Phase I clinical investigation of PHP in conjunction with high-dose IL-2 treatment to evaluate safety of this compound and to establish an effective dose. In Specific Aim 1 we will assess the safety of PHP in patients with metastatic renal carcinoma or malignant melanoma. This study will establish dose-limiting toxicity (if any) of this agent in combination with high dose IL-2, and define a biologically effective dose for reversal of IL-2 induced hypotension. In Specific Aim 2 we will determine the effect of PHP on hemodynamic function in IL-2 treated patients, including assessment of blood pressure, systemic vascular resistance, cardiac index, pulmonary artery pressure and capillary wedge pressure and the total dose of pressors required during each course of high-dose IL-2. In Specific Aim 3, we will assess the potential usefulness of intermediate biomarkers for activation of the nitric oxide synthesis pathway in patients treated with IL-2 with or without PHP, to develop assays for phase II testing. It should be stressed that knowledge gained from evaluation of mechanisms of IL-2 toxicity is likely to be broadly relevant to understanding the pathophysiology of hypotension and vascular leak induced by other cytokines, such as IL-1, TNF, VEGF and IL-12.

描述（由申请人提供）： 高剂量 IL-2 可使一小部分（5-10%）转移性肾癌或黑色素瘤患者完全缓解。有趣的是，许多 IL-2 诱导的完全缓解已被证明是持久的，随访时间长达 18 年。 IL-2的临床使用受到严重副作用的限制，特别是低血压和“血管渗漏综合征”(VLS)。使用高剂量 IL-2 治疗的患者需要住院进行密切监测，并给予液体、胶体和升压药物，以治疗剂量依赖性的低血压。由于心血管毒性，计划的 IL-2 剂量的很大一部分（1/3 至 1/2）通常被省略，这可能会影响有效性。我们的实验室和临床研究表明，IL-2 治疗后会强烈诱导一氧化氮 (NO) 的合成。 NO是低血压和血管渗漏的重要介质。我们最近发现了一种有前途的新药 PHP，它是一种吡哆醛化血红蛋白聚氧乙烯结合物，它似乎对人类是安全的，并且由于其分解代谢 NO 以及其他物质的能力，有可能预防 IL-2 引起的低血压和 VLS。潜在有害的氧化自由基。该拨款申请旨在支持 PHP 与高剂量 IL-2 治疗相结合的 I 期临床研究，以评估该化合物的安全性并确定有效剂量。在具体目标 1 中，我们将评估 PHP 在转移性肾癌或恶性黑色素瘤患者中的安全性。本研究将确定该药物与高剂量 IL-2 联合使用时的剂量限制毒性（如果有），并确定逆转 IL-2 引起的低血压的生物学有效剂量。在具体目标 2 中，我们将确定 PHP 对 IL-2 治疗患者血流动力学功能的影响，包括评估血压、全身血管阻力、心脏指数、肺动脉压和毛细血管楔压以及每次治疗期间所需的升压药总剂量。高剂量IL-2疗程。在具体目标 3 中，我们将评估中间生物标志物在联合或不联合 PHP 治疗的患者中激活一氧化氮合成途径的潜在用途，以开发 II 期测试的测定方法。应该强调的是，从 IL-2 毒性机制评估中获得的知识可能与理解其他细胞因子（如 IL-1、TNF、VEGF 和 IL-12）引起的低血压和血管渗漏的病理生理学广泛相关。