A Phase I study of a dual PI3K/BRD4 inhibitor, SF1126 in the treatment of hepatocellular carcinoma | IDE: 74,551

PI3K/BRD4 双重抑制剂 SF1126 治疗肝细胞癌的 I 期研究 |

• 批准号: 9167160
• 负责人: DONALD DURDEN
• 金额: $ 25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167160
• 关键词: Phase; study; dual; PI3K; BRD4

Hepatocellular carcinoma (HCC) accounts for 80-90%of liver cancer diagnosed in adult oncology and thus accounts for significant morbidity and mortality in the United States. A major mechanism of HCC resistance and ability of cancer cells to thwart treatments relies on the PI-3 kinase and Myc cell signaling pathways. We have generated preliminary data which suggest that a dual pan PI-3 kinase/BRD4 inhibitor, SF1126 has potent antitumor activity in vitro and in vivo against HCC and inhibits the BRD4-Myc interaction. These data support the hypothesis that dual PI3K/BRD4 inhibitors will have activity in the treatment of advanced HCC. Based on SEER database published in 2010 (www.SEER.org) the prevalence of HCC is 41,404 in the US. Currently, the only curative treatment for HCC is complete surgical resection or liver transplantation. The significance of our proposal derives from the unmet medical need for alternative therapy for patients with recurrent, unresectable, and/or metastatic HCC (termed advanced HCC). If successful, this therapy could provide a significant advancement in the quality of treatment and quality of life for this difficult to treat disease. A previous Phase I trial of a dual PI3K/BRD4 inhibitor, SF1126 (an integrin targeted prodrug small molecule) (partly supported by the NIH RO1 CA94233) was carried out in 39 non-genotyped patients diagnosed with recurrent adult solid tumors (including colon cancer, renal cell carcinoma, and recurrent breast cancer) and 5 patients with B-cell malignancy. SF1126 was well-tolerated and demonstrated complete pathway inhibition in tumor biopsies. Importantly, SF1126 displayed no hepatotoxicity in this Phase I trial. Clinical benefit was observed in the form of prolonged stable disease for up to 84 weeks duration. Stable disease was the best response in 19 of 33 patients (58%) evaluable patients with median duration of 13 weeks and mean of 18 weeks. MTD was not reached but the maximum administered dose (MAD) after 9 dose escalation cohorts was 1110 mg/m2 and this dose was chosen as the recommended Phase II dose (RMP2). The results of the Phase I trial justify a Phase I evaluation of SF1126 in HCC. We propose 3 specific aims to test the hypothesis that SF1126 will be efficacious in advanced HCC. The specific aims are designed: 1) to determine the toxicity profile of SF1126 in order to determine the RMP2 dose level in the treatment of advanced HCC patients including patients classified as Child-Pugh A-B7 with liver dysfunction/cirrhosis; 2) to evaluate mechanisms of resistance in HCC cell lines and tumor models and 3) to validate and compare the observed resistance mechanisms confirmed in Aim 2-3 to the TCGA-ICGC molecular and clinical dataset of 1094 HCC tumors in preparation for planned Phase II trial. An innovative component of this proposal derives from this being one of the first clinical trials of a novel PI-3 kinase/BRD4 inhibitor in a Phase I HCC trial and our efforts to use sophisticated molecular methods to identify a molecular signature in HCC model systems which may identify factors which define resistance or sensitivity to this class of agent in future Phase II trials.

肝细胞癌（HCC）占成年肿瘤学诊断的肝癌的80-90％，因此占 在美国，发病率和死亡率很大。 HCC抗性的主要机制和 癌细胞阻碍治疗的能力取决于PI-3激酶和MYC细胞信号通路。我们有 生成的初步数据表明双PAN PI-3激酶/BRD4抑制剂SF1126具有有效 抗肿瘤活性在体外和体内对HCC的体内，并抑制BRD4-MYC相互作用。这些数据支持 假设双PI3K/BRD4抑制剂将在治疗晚期HCC方面具有活性。基于先知 2010年发布的数据库（www.seer.org）在美国，HCC的患病率为41,404。目前，唯一的 HCC治疗治疗是完全手术切除或肝移植。我们提议的意义 源自未满足的医疗需求，可用于复发，不可切除和/或的患者 转移性HCC（称为高级HCC）。如果成功，这种疗法可以在 这种难以治疗疾病的治疗质量和生活质量。上一阶段的I二次试验 PI3K/BRD4抑制剂SF1126（整合素靶向前药小分子）（部分由NIH RO1支撑 CA94233）在39例被诊断为复发成人实体瘤的非生成类型患者中进行（包括 结肠癌，肾细胞癌和复发性乳腺癌）和5例B细胞恶性肿瘤患者。 SF1126 在肿瘤活检中得到了良好的耐受性，并证明了完全的途径。重要的是，SF1126 在此I阶段试验中没有显示肝毒性。以延长的稳定形式观察到临床益处 疾病长达84周。稳定疾病是33例患者中有19例（58％）的最佳反应 中位持续时间为13周，平均值为18周的患者。 MTD未达到，但最大 9剂量升级队列后的剂量（MAD）为1110 mg/m2，选择该剂量为 推荐的II期剂量（RMP2）。第一阶段试验的结果证明了对SF1126的I期评估 HCC。我们提出了3个特定的目的，以检验SF1126在高级HCC中有效的假设。这 设计了具体目的：1）确定SF1126的毒性特征以确定RMP2剂量 治疗高级HCC患者的水平，包括分类为肝脏的儿童PUGH A-B7的患者 功能障碍/肝硬化； 2）评估HCC细胞系和肿瘤模型中耐药机制，以及3） 验证并比较在AIM 2-3中确认的观察到的电阻机制与TCGA-ICGC分子 和1094个HCC肿瘤的临床数据集为计划的II期试验做准备。这个创新的组成部分 提案源自该提案是I期在I期的新型PI-3激酶/BRD4抑制剂的首次临床试验之一 HCC试验以及我们使用复杂的分子方法来识别HCC模型中的分子签名的努力 可以确定在未来II期中定义抗药性或对这类代理的敏感性的因素 试验。