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）占成人肿瘤学诊断的肝癌的80- 90%，因此 在美国造成了很大的发病率和死亡率。肝癌耐药的主要机制， 癌细胞阻碍治疗的能力依赖于PI-3激酶和Myc细胞信号传导途径。我们有 产生的初步数据表明，双泛PI-3激酶/BRD 4抑制剂SF 1126具有有效的 在体外和体内抗HCC的抗肿瘤活性，并抑制BRD 4-Myc相互作用。这些数据支持 假设双重PI 3 K/BRD 4抑制剂将在晚期HCC的治疗中具有活性。基于SEER 2010年发布的数据库（www.SEER.org）显示，美国HCC的患病率为41，404例。目前，唯一 HCC的治愈性治疗是完全手术切除或肝移植。我们提议的重要性 源自复发性、不可切除和/或 转移性HCC（称为晚期HCC）。如果成功的话，这种疗法可能会在以下方面取得重大进展： 这种难以治疗的疾病的治疗质量和生活质量。之前的一项双重I期试验 PI 3 K/BRD 4抑制剂，SF 1126（一种靶向整联蛋白的前药小分子）（部分得到NIH RO 1的支持 CA 94233）在39名诊断为复发性成人实体瘤的非基因分型患者（包括 结肠癌、肾细胞癌和复发性乳腺癌）和5名B细胞恶性肿瘤患者。SF1126 耐受性良好，并在肿瘤活检中显示出完全的途径抑制。重要的是，SF 1126 在I期试验中没有显示肝毒性。观察到的临床获益是长期稳定的 病程长达84周。33例可评价患者中有19例（58%）的最佳缓解为疾病稳定。 患者中位持续时间为13周，平均18周。未达到MTD，但已达到最大值 9个剂量递增队列后的平均给药剂量（MAD）为1110 mg/m2，选择该剂量作为 II期推荐剂量（RMP 2）。I期试验的结果证明了SF 1126在 HCC。我们提出了3个具体的目标来检验SF 1126对晚期HCC有效的假设。的 具体目标是：1）确定SF 1126的毒性特征，以确定RMP 2剂量 治疗晚期HCC患者的水平，包括Child-Pugh A-B 7级肝硬化患者 功能障碍/肝硬化; 2）评估HCC细胞系和肿瘤模型中的抗性机制和3） 验证并比较目标2-3中确认的观察到的耐药机制与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。其中一个创新的组成部分是 该提案源于这是一种新型PI-3激酶/BRD 4抑制剂在I期临床试验中的首批临床试验之一。 HCC试验和我们努力使用复杂的分子方法来识别HCC模型中的分子特征 在未来的第二阶段中，可以确定确定对这类药剂的抗性或敏感性的因素的系统 审判