Exclusion criteria included: women who have been pregnant or nursing; treatment with radiotherapy or chemotherapy within 4 weeks; major surgery treatment within 3 weeks; known central nervous system metastasis requiring anticonvulsants or steroids; patients on restorative anticoagulation not on stable dosages; uncontrolled severe cardiac disease or diabetes mellitus; any medical condition that would impair administration of an oral medication; prior mTOR and / or IGF1R therapies and uncontrolled severe medical or psychiatric illness

Exclusion criteria included: women who have been pregnant or nursing; treatment with radiotherapy or chemotherapy within 4 weeks; major surgery treatment within 3 weeks; known central nervous system metastasis requiring anticonvulsants or steroids; patients on restorative anticoagulation not on stable dosages; uncontrolled severe cardiac disease or diabetes mellitus; any medical condition that would impair administration of an oral medication; prior mTOR and / or IGF1R therapies and uncontrolled severe medical or psychiatric illness. The protocol was approved by the institutional review board at M.D Anderson Malignancy Center, and written informed consent was obtained for those Furagin patients prior to performing study-related methods in accordance with federal and institutional recommendations. Study Design This was a single institution, single arm, inter-patient dose escalation study having a dose expansion cohort of 9 patients enrolled in the recommended dose. was enrolled at RP2D. Correlative studies included evaluation of mTOR pathway inhibition in Furagin combined tumor biopsies and effects of this combination on rate of metabolism per indirect calorimetry. 19 individuals with progressive disease, including 9 to the development portion were enrolled. 2 individuals had dose limiting toxicities of grade 3 mucositis at cixutumumab 15 mg/kg. Long term tolerance at RP2D was problematic, the most common grade 3 adverse event (AE) becoming fatigue. One individual with metastatic insulinoma experienced a confirmed partial response while seventeen experienced stable disease. Median progression free survival was 43.6 weeks and median overall survival was 25.5 months. Conclusions The RP2D of this combination per predefined study protocol cixutumumab iv 10 mg/kg, octreotide LAR 20 mg IM every 21 days plus everolimus 10 mg po daily is definitely associated with non-DLT toxicities limiting long term tolerance. Although a signal of activity was mentioned with this study, this will need to become reconciled with limited tolerance of the combination and data from larger studies of anti-IGF-1R monoclonal antibodies in NET that have been disappointing. Introduction The incidence of neuroendocrine tumors (NETs) offers Furagin improved from 1.09 cases per 100,000 in 1973 to 5.25 per 100,000 in 2004 (Yao, et al. 2008). While often slow growing, these cancers are however incurable and lethal when advanced. However, treatment options continue to be limited, especially for carcinoid tumors. Mutations in the mammalian target of rapamycin (mTOR) pathway have been reported in 14% of pNETs and such abnormalities have also been associated with more aggressive tumors (Jiao, et al. 2011; Meric-Bernstam and Gonzalez-Angulo 2009). The phase III randomized, placebo-controlled RADIANT-3 study showed significant improvement in progression free survival (PFS) with everolimus, an oral inhibitor of mTOR in individuals with pancreatic NETs (Yao, et al. 2011). Another placebo-controlled phase III study, RADIANT-2 randomized individuals with advanced neuroendocrine tumors associated with carcinoid syndrome to octreotide long-acting repeatable (LAR) in combination with placebo or everolimus and showed improved PFS in the everolimus arm although this did not meet the predefined threshold for significance (Pavel, et al. 2011). IGF-1R receptors and ligands are known to be indicated at higher concentrations in NETs than in normal cells (Wulbrand, et al. 2000). Studies in carcinoid cell lines display that IGF1 is definitely a major regulator of neuroendocrine secretion and growth (von Wichert, et al. 2000). Additional studies have shown that blockade of IGF1R results in Furagin inhibition of NET cells growth and induction of apoptosis (Hopfner, et al. 2006). Mouse models of pancreatic neuroendocrine tumors suggest a role for the insulin growth element-2, IGF2 in tumorigenesis (Christofori, et al. 1995). Finally, additional preclinical studies have suggested that IGF-1 protects malignancy cells from rapamycin-induced cell death and that inhibition of IGF-1R prevents rapamycin-induced AKT activation and sensitizes tumor cells to mTOR inhibitors therefore providing a rationale for combined blockade of these pathways (O’Reilly, et al. 2006; Thimmaiah, et al. 2003). The goals of this phase I study were to establish the security and RP2D of everolimus and octreotide LAR in combination with escalating doses of the anti-IGF1R monoclonal antibody, and to evaluate for preliminary evidence of activity in individuals with advanced, low to intermediate grade NETs. Individuals and Methods Eligibility criteria Eligible individuals experienced progressive, advanced or Akt3 metastatic low or intermediate grade neuroendocrine cancers (carcinoid of any site or pNET) refractory to or without standard therapy options, evaluable or measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors) (Therasse, et al. 2000) and Eastern Cooperative Oncology Group (ECOG) overall performance status of 0-1. Individuals may have received previous therapy (except mTOR inhibitors or providers targeting IGF1R) with no limitation on the number of previous regimens. Individuals also had to be age 18 years or older with adequate hematopoietic, hepatic and kidney function; fasting serum glucose 132 mg/dl and fasting serum cholesterol 300 mg/dl and fasting triglycerides 375 mg / dl. Exclusion criteria included: women who have been pregnant or nursing; treatment with radiotherapy or chemotherapy within 4 weeks; major surgery treatment within 3 weeks; known central nervous system metastasis requiring anticonvulsants or steroids; individuals on restorative anticoagulation not on stable dosages; uncontrolled severe cardiac disease or diabetes mellitus; any medical condition that would impair administration of an oral medication; prior mTOR and / or IGF1R therapies and uncontrolled severe medical or psychiatric illness. The protocol was authorized by the institutional review table at M.D Anderson Malignancy Center, and written informed consent was obtained for those individuals prior to.