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

描述（由申请人提供）： 高剂量IL-2在小比例（5-10%）的转移性肾癌或黑色素瘤患者中产生完全缓解。有趣的是，许多IL-2诱导的完全缓解已被证明是持久的，随访长达18年。IL-2的临床应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）。用高剂量IL-2治疗的患者需要住院以密切监测和施用流体、胶体和升压药物，以治疗以剂量依赖性方式发生的低血压。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，这可能会损害有效性。我们的实验室和临床研究表明，一氧化氮（NO）的合成强烈诱导IL-2治疗后。一氧化氮是低血压和血管渗漏的重要介质。我们最近已经确定了一种有前途的新药物，PHP，吡哆醛血红蛋白聚氧乙烯共轭物，似乎是安全的，在人类中，并有可能防止IL-2诱导的低血压和VLS由于其分解代谢NO的能力，以及其他潜在的有害氧化自由基。该资助申请旨在支持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联合使用的剂量限制性毒性（如有），并确定逆转IL-2诱导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治疗患者的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在高剂量IL-2的每个疗程期间所需的升压剂的总剂量。在具体目标3中，我们将评估中间生物标志物在IL-2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有用性，以开发II期试验的检测方法。应该强调的是，从评价IL-2毒性机制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）诱导的低血压和血管渗漏的病理生理学广泛相关。

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.