PHASE I EVALUATION OF RTNF PLUS RIFN-GAMMA IN PATIENTS WITH SOLID TUMORS

RTNF 加 RIFN-γ 在实体瘤患者中的 I 期评估

• 批准号: 3916683
• 负责人: R G STEIS
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3916683
• 关键词: biological response modifiers; combination cancer therapy; combination chemotherapy; cytotoxicity; disease /disorder model; drug adverse effect; granulocytopenia; human subject; human therapy evaluation; immunomodulators; immunotoxicity; interferons; neoplasm /cancer immunotherapy; thrombocytopenia; tumor necrosis factor alpha

Clinical trials using single agent tumor necrosis factor have been ongoing for approximately the past 2 years. In vitro studies with TNF have demonstrated that the combination of interferon-gamma with tumor necrosis factor results in significant augmentation of antitumor effects. These results have been confirmed in vivo in animal models, however, it is not known if this enhancement is due to augmentation of the immune system. Substantial enhancement of TNF-related toxicity has also been observed using this drug in combination with interferon-gamma. In this study, we intend to investigate the immunomodulatory and toxic effects of the combination of TNF and interferon-gamma. Thirty-six patients have been treated on this study at nine different dose levels. Toxicities observed so far include fever, chills, headache, myalgia, fatigue, anorexia, nausea, vomiting, paresthesias, pain and erythema at the injection site of rTNF, moderate granulocytopenia and thrombocytopenia, moderate elevation in liver enzymes, and increases in fasting serum triglyceride levels. One patient experienced a mild cerebral infarct and was removed from the study. At dose level 9 (100 mcg/ml IFN-gamma/l00 mcg/ml rTNF), one patient had grade 4 fever, and another patient had grade 3 thrombocytopenia. The dose immediately below that, dose level 8, (100 mcg/ml rIFN-gamma/50 mcg/ml rTNF) was established as the maximum tolerated dose which should be investigated further in phase II trials. Minor antitumor activity was noted in two patients. An important finding of this study was the rTNF induced blunting of the expected monocyte activation by rIFN-gamma. No synergistic immunological effects were noted. Although enhanced immunomodulating effects were not observed, synergistic antitumor effects based on other mechanisms still may be observed in future phase II trials.

使用单一药物肿瘤坏死因子的临床试验已经 持续了大约两年。 的体外研究 TNF已经证明干扰素-γ与 肿瘤坏死因子可显著增强 抗肿瘤作用 这些结果已经在体内证实， 然而，在动物模型中，尚不清楚这种增强是否是由于 增强免疫系统。 大幅度提高 TNF相关的毒性也被观察到使用这种药物， 与干扰素-γ的组合。 在这项研究中，我们打算 研究免疫调节和毒性作用的 TNF和干扰素-γ的组合。 在这项研究中，36名患者在9岁时接受了治疗。 不同的剂量水平。 迄今为止观察到的毒性包括发烧， 寒战、头痛、肌痛、疲劳、厌食、恶心、呕吐， rTNF注射部位的感觉异常、疼痛和红斑， 中度粒细胞减少症和血小板减少症，中度升高 肝酶和空腹血清甘油三酯增加 程度. 1例患者发生轻度脑梗死， 从研究中删除。 在剂量水平9（100 mcg/ml IFN-γ/100 mcg/ml rTNF），1例患者出现4级发热，另1例患者出现4级发热， 患有3级血小板减少症。 低于这个剂量， 剂量水平8（100 mcg/ml rIFN-γ/50 mcg/ml rTNF）， 确定为最大耐受剂量， 在II期试验中进一步研究。 轻微抗肿瘤活性 在两名患者中观察到。 这项研究的一个重要发现是， rTNF诱导预期的单核细胞活化钝化， rIFN-γ 未观察到协同免疫效应。 虽然没有观察到增强的免疫调节作用， 基于其它机制的协同抗肿瘤作用仍然可以 在未来的第二阶段试验中观察。