Clinical Study of PHY906, a Novel Chinese Herbal Medicine, as a Modulator of Irin

PHY906是一种传统的中草药，在东方已有近2000年的历史，用于治疗腹泻和恶心/呕吐。我们的研究小组已经开发出一种新的cGMP配方的PHY906，已被证明是不含重金属和任何其他污染物。我们已经描述了PHY906作为抗癌药物的细胞毒性调节剂和化疗的细胞保护剂的临床前活性。一系列使用小鼠异种移植模型的临床前体内研究表明，这种草药可以增强多种抗癌药物的抗肿瘤活性，包括topo I抑制剂伊立替康，并降低毒性。一项初始i / la期临床研究的初步结果显示，PHY906联合IFL化疗一线治疗晚期结直肠癌患者，能够有效降低腹泻和恶心/呕吐的Gl毒性以及整体疲劳。这些观察结果表明，PHY906可以降低伊立替康化疗相关的毒性。然而，这项初步的先导研究无法确定PHY906对伊立替康化疗临床疗效的潜在影响。我们的假设是，PHY906将能够增强与伊立替康化疗相关的安全性，并维持（如果不能改善的话）与这种抗癌药物相关的临床活性。为了直接验证这一假设，我们计划开展一项随机、双盲、安慰剂对照的II期临床试验，研究中草药PHY906对伊立替康单药治疗晚期结直肠癌二线患者的毒性、生活质量和临床疗效的影响。患者将被随机分配到伊立替康加安慰剂的对照组或伊立替康加PHY906的实验组。作为该临床研究的一部分，提出了3个具体目标：目标1将确定PHY906对伊立替康单药治疗安全性的影响，重点是Gl毒性，以腹泻和恶心/呕吐的形式，以及骨髓抑制和疲劳。目的2将研究PHY906对伊立替康单药治疗相关的总体生活质量的影响，使用完善且经过验证的患者报告评估工具。目的3将研究PHY906对伊立替康单药治疗临床疗效的影响，包括总缓解率、无进展生存期和总生存期。

PHY906 is a traditional Chinese herbal medicine that has been used in the Orient for nearly 2000 years to treat diarrhea and nausea/vomiting. Our research group has developed a novel cGMP formulation of PHY906 that has been shown to be free of heavy metals and any other contaminants. We have characterized the preclinical activity of PHY906 as a modulator of cytotoxicity of anticancer agents and a cytoprotective agent of chemotherapy. An extensive series of pre-clinical in vivo studies using mouse xenograft models have shown that this herbal medicine can enhance the antitumor activity of a broad range of anticancer agents, including the topo I inhibitor irinotecan, and reduce toxicity. Preliminary results from an initial phase l/lla clinical study with PHY906 in combination with IFL chemotherapy in the front-line treatment of advanced CRC patients showed that PHY906 was able to effectively reduce the Gl toxicities of diarrhea and nausea/vomiting as well as overall fatigue. These observations suggested that PHY906 can reduce the toxicities associated with irinotecan-based chemotherapy. However, this initial pilot study was unable to determine the potential effect of PHY906 on the clinical efficacy of irinotecan chemotherapy. Our hypothesis is that PHY906 will be able to enhance the safety profile associated with irinotecan chemotherapy and maintain, if not improve, the clinical activity associated with this anticancer agent. To directly address this hypothesis, we plan to conduct a randomized, double-blind, placebo-controlled phase II clinical trial to investigate the effects ofthe Chinese herbal medicine PHY906 on the toxicity, quality of life, and clinical efficacy of irinotecan monotherapy in the treatment of patients with advanced CRC in the second-line setting. Patients will be randomized to receive the control arm of irinotecan plus placebo or to the experimental arm of irinotecan plus PHY906. As part of this clinical study, 3 specific aims are proposed: Aim 1 will determine the effect of PHY906 on the safety profile of irinotecan monotherapy with a focus on Gl toxicity, in the form of diarrhea and nausea/vomiting, as well as myelosuppression and fatigue. Aim 2 will investigate the effect of PHY906 on overall quality of life associated with irinotecan monotherapy using well-established and validated patient-reported assessment tools. Aim 3 will investigate the effect of PHY906 on the clinical efficacy of irinotecan monotherapy with respect to overall response rates, progression-free survival, and overall survival.