This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT This is a Phase I combination study of IMC-A12, a recombinant monoclonal antibody to the insulin-like growth factor receptor (IGFR) in combination with temsirolimus, an mTOR inhibitor in children and adolescents with recurrent or refractory solid tumors. IMC-A12 is a fully recombinant IgG1 monoclonal antibody that specifically targets the human IGF-IR1 with high affinity. It acts as an antagonist of IGF-1 and IGF-2 ligand binding and signaling and blocks ligand binding to IGF-IR and inhibits downstream signaling of the two major insulin-like growth factor pathways: MAPK and PI3K/AKT. IMC-A12 has potent in vitro and in vivo activity in a variety of cell-lines and xenografts, in a dose dependent manner. Immunohistochemical analysis of treated xenografts demonstrated that the IMC-A12 led to suppression of IGFIR signaling, degradation of the surface receptor on tumor cells, and increased the number of apoptotic cells relative to untreated controls. Temsirolimus is a small molecule inhibitor of mTOR. Like rapamycin and everolimus, temsirolimus forms a complex with FK506-binding protein (FKBP)12 and mTOR, inhibiting mTOR and leading to antiproliferative effects, including G1 phase cell cycle arrest and apoptosis.3 The primary downstream targets of mTOR include eIF4E binding protein (4E-BP1)4,5 and p70S6 kinase important in the translation regulation of mRNA encoding proteins involved in G1 phase progression. The Mtor inhibitors have potent in vitro activity against many human cancer cell lines and xenograft models. Furthermore, rapamycin analogues are highly lipophilic and can cross the blood brain barrier. Inhibition of mTOR signaling leads to upregulation of IGF-1R signaling through stabilization of IRS1. This leads to activation of the PIK3/AKT/mTOR pathway.Inhibition of mTOR stabilizes IRS1 resulting in AKT activation in cancer cell lines and in patients treated with mTOR inhibitors, such as rapamycin, temsirolimus or RAD001. The combination of an IGF-1R targeted antibody (CP751871) and rapamycin demonstrated synergistic activity in 5 of 6 childhood sarcoma xenograft models.24 In this Phase I trial the maximum tolerated dose of IMC-A12 in combination with temsirolimus will be determined in patients with solid tumors. Patients with recurrent or refractory solid tumors will be eligible if they have adequate hematologic, hepatic, renal, and pulmonary status. IMC-A12 and temsirolimus will be administered weekly. A cycle of therapy is considered to be 28 days. I. HYPOTHESIS We propose a Phase I trial of IMC-A12 (anti-IGF-1R monoclonal antibody) in combination with CCI-779 (temsirolimus), an mTOR inhibitor in patients with solid tumors. If a patient has clearly progressive disease, s/he will be removed from protocol therapy. If there is a response or stable disease, the patient can continue to receive up to 25 cycles of therapy, for a total duration of therapy of 2 years. II.
SPECIFIC AIMS Primary Aims 1. To estimate the maximum tolerated dose (MTD) and recommended Phase II dose of IMC-A12 (anti-insulin growth factor-1 receptor monoclonal antibody) administered as an intravenous infusion once weekly in combination with CCI- 779 (temsirolimus) administered intravenously once weekly to children with refractory solid tumors. 2. To define and describe the toxicities of IMC-A12 in combination with temsirolimus administered on this schedule. 3. To characterize the pharmacokinetics of IMC-A12 in combination with temsirolimus in children with refractory cancer. Secondary Aims 1. To preliminarily define the antitumor activity of the combination of IMC-A12 and temsirolimus within the confines of a Phase I study. 2. To assess the biologic activity of IMC-A12 by assessing: (a) changes in IGFR expression and phosphorylation and (b) insulin receptor expression and phosphorylation in peripheral blood mononuclear cells (PBMNC). 3. To assess the biological activity of temsirolimus by measuring levels of phosphor-S6Ser235/236, phosphor-AKTSer473, and phosphor-eIF4G ser1108 in PBMNC.
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