PHASE II TRIAL OF IL-1 ALPHA + INDOMETHACIN IN MELANOMA PATIENTS

IL-1 α具有抗人黑色素瘤细胞增殖活性 线，导致小鼠黑色素瘤肿瘤缩小体内，可以诱导 干扰素和白细胞介素-2，它们在黑色素瘤中具有活性， 增强细胞毒性T细胞和其它效应细胞的活性。 动物研究表明，吲哚美辛增加了抗肿瘤作用， IL-1的作用。 出于这些原因，我们设计了这项II期研究， 黑色素瘤患者，以确定IL-1 α加 吲哚美辛使用最大耐受剂量的IL-1 α， 第一阶段试验。 共有49名患者进入研究， 并且都可以评估反应。 14名患者中， 主要是内脏转移对治疗有反应。 的35 非内脏转移的患者中，4例患者应答（1例CR，3例 PR）的应答率为11%（95%置信区间：5-26%）。 这些 结果表明IL-1 α在黑素瘤中具有低水平的活性。 为了加强这项活动，我们修改了这项试验，以结合联合收割机 依托泊苷（VP-16）与该方案基于临床前研究， 证明了与组合的协同抗肿瘤作用。 的 迄今为止入组了13例患者，其中11例可评价，无应答。

IL-1alpha has antiproliferative activity against human melanoma cell lines, causes murine melanoma tumors to shrink in vivo, can induce interferons and interleukin-2 which have activity in melanoma, and can enhance the activity of cytotoxic T cells and other effector cells. Animal studies suggested that indomethacin increased the antitumor effects of IL-1. For these reasons, we designed this phase II study in melanoma patients to determine the anti-tumor activity of IL-1alpha plus indomethacin using the maximum tolerated dose of IL-1alpha from our earlier phase I trial. A total of 49 patients have entered the study, and all are evaluable for response. None of the 14 patients with predominately visceral metastases responded to treatment. Of the 35 patients with non-visceral metastases, four patients responded (1 CR, 3 PR) for a response rate of 11% (95% confidence interval: 5-26%). These results indicate that IL-1alpha has a low level of activity in melanoma. In an effort to enhance this activity, we amended this trial to combine etoposide (VP-16) with this regimen based on preclinical studies that demonstrated synergistic antitumor effects with the combination. Of the 13 patients enrolled to date, 11 are evaluable and none have responded.