Phase I Study of IMC-A12 in Combination with Temsirolimus

描述（由申请人提供）：雷帕霉素的哺乳动物靶标（mTOR）是PI 3 K/AKT/mTOR通路的重要效应物，参与调节促进肿瘤发生的许多细胞过程，如癌细胞存活、增殖和生长。PI 3 K/AKT/mTOR通路通常由上游受体酪氨酸激酶，特别是胰岛素受体和胰岛素样生长因子-1受体（IGF-1 R）调节。最近的体外和体内研究以及来自患者的肿瘤活检结果已经证明，用mTOR抑制剂治疗导致肿瘤中AKT磷酸化的上调。鉴于AKT活化导致恶性表型增加，磷酸化AKT（pAKT）的诱导是mTOR抑制的不期望的结果，拮抗mTOR抑制剂的抗增殖作用。几项研究表明，mTOR抑制剂通过IGF-1 R依赖性机制介导AKT活化，IGF-1 R抑制剂可消除或减少mTOR抑制剂诱导的pAKT。因此，将IGFR抑制剂与mTOR抑制剂组合可以克服AKT介导的肿瘤逃逸/抗性。 我们将进行mTOR抑制剂替西罗莫司（CCI-779）和IGF-1 R抑制剂单克隆抗体IMC-A12组合的首次研究。本方案是应国家癌症研究所-癌症治疗评估计划（NCI-CTEP）的要求制定的，并已获得NCI-CTEP的批准。 本项目的主要研究目的是评价IMC-A12和替西罗莫司联合给药后晚期恶性肿瘤患者的抗肿瘤/生物活性的药效学标志物。 将对患者进行随访，以评价IMC-A12和替西罗莫司的毒性、耐受性和临床益处。我们将通过反相蛋白阵列、免疫组织化学评价药效学标志物，包括IGF-1 R和PI 3 K/AKT/mTOR通路中的pAKT和信号组分，以及通过2[18 F]氟-2-脱氧-D-葡萄糖正电子发射断层扫描评价肿瘤葡萄糖代谢的早期变化。这些研究的结果将纳入IMC-A12 +替西罗莫司扩展临床试验的设计中。 公共卫生相关性：这项试验的结果将提供关于肿瘤对药物的耐药性以及可用于克服这种耐药性的策略的进一步见解。更好地了解肿瘤代谢检测的非侵入性成像也将划定。 拟议的研究有可能成为IGF-R和mTOR抑制剂（包括小分子IGF-R抑制剂）未来组合的签名试验，并提供数据以定义此类试验的最佳相关终点。本方案中测试的药物组合有望在随后的II期试验中为乳腺癌、肉瘤和胰腺等肿瘤类型提供广泛的适用性。

DESCRIPTION (provided by applicant): The Mammalian target of rapamycin (mTOR) is a vital effector of the PI3K/AKT/mTOR pathway involved in regulating many cellular processes that promote tumorigenesis such as cancer cell survival, proliferation, and growth. The PI3K/AKT/mTOR pathway is normally regulated by upstream receptor tyrosine kinases, especially insulin receptor and insulin-like growth factor-1 receptor (IGF-1R). Recent in vitro and in vivo studies, as well as tumor biopsy results from patients, have demonstrated that treatment with mTOR inhibitors leads to upregulation of AKT phosphorylation in tumors. Given that AKT activation results in increased malignant phenotype, the induction of phosphorylated AKT (pAKT) is an undesirable consequence of mTOR inhibition, antagonizing the anti-proliferative effects of mTOR inhibitors. Several studies have shown that mTOR inhibitors mediate AKT activation through an IGF-1R-dependent mechanism and that IGF-1R inhibitors may abrogate or reduce pAKT induced by mTOR inhibitors. Therefore, combining an IGFR inhibitor with an mTOR inhibitor could overcome AKT-mediated tumor escape/ resistance. We will perform the first study of the combination of the mTOR inhibitor temsirolimus (CCI-779) and the IGF-1R Inhibitor monoclonal antibody IMC-A12. This protocol was developed in response to a National Cancer Institute-Cancer Therapeutics Evaluation Program (NCI-CTEP) solicitation and has been approved by NCI-CTEP. The primary research objective of this project is to evaluate pharmacodynamic markers of the antitumor/biologic activity of IMC-A12 and temsirolimus upon combined administration to patients with advanced malignancies. Patients will be followed for evaluation of toxicity, tolerability and clinical benefit of IMC-A12 and temsirolimus. We will evaluate pharmacodynamic markers including pAKT and signaling components in the IGF-1R and PI3K/AKT/mTOR pathways by reverse phase protein array, immunohistochemistry, as well as early changes in tumor glucose metabolism by 2[18F]fluoro-2-deoxy-D-glucose Positron Emission Tomography. The results of these studies will be incorporated into designs for expanded clinical trials with IMC-A12 + temsirolimus. PUBLIC HEALTH RELEVANCE: The results of this trial will provide further insight regarding tumor resistance to drugs as well as strategies that can be used to overcome such resistance. A better understanding of tumor metabolism detected by non-invasive imaging will also be delineated. The proposed study has the potential to be a signature trial for future combinations of IGF-R and mTOR inhibitors, including small molecule IGF-R inhibitors, and to provide data to define the optimum correlative endpoints for such trials. The drug combination tested in this protocol has the promise of providing broad applicability for tumor types such as breast, sarcoma and pancreas in subsequent phase II trials.