Phase I Study of IMC-A12 in Combination with Temsirolimus

描述（由申请人提供）：哺乳动物雷帕霉素靶点（mTOR）是PI3K/AKT/mTOR通路的重要效应物，参与调节许多促进肿瘤发生的细胞过程，如癌细胞存活、增殖和生长。PI3K/AKT/mTOR通路通常受上游受体酪氨酸激酶的调控，尤其是胰岛素受体和胰岛素样生长因子-1受体（IGF-1R）。最近的体外和体内研究以及患者的肿瘤活检结果表明，使用mTOR抑制剂治疗可导致肿瘤中AKT磷酸化的上调。鉴于AKT激活导致恶性表型增加，诱导磷酸化AKT （pAKT）是mTOR抑制的不良后果，可拮抗mTOR抑制剂的抗增殖作用。多项研究表明，mTOR抑制剂通过依赖IGF-1R的机制介导AKT活化，IGF-1R抑制剂可以消除或减少mTOR抑制剂诱导的pAKT。因此，IGFR抑制剂与mTOR抑制剂联合使用可以克服akt介导的肿瘤逃逸/抵抗。

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.