Abstract
Abstract Background: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), on the basis of preclinical data suggesting that the combination could overcome resistance in Ewing's sarcoma (EWS). Methods: Patients received cixutumumab, 6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Median follow up was 8.9 months. Results: Twenty patients (17 with EWS, 3 with desmoplastic small-round-cell tumor [DSCRT]) were enrolled. Twelve patients (60%) were men; median age, 24 years; median number of prior therapies, 6. Six patients previously received an IGF-1R inhibitor and two, temsirolimus. The most frequent toxicities, at least possibly drug-related, were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%) (mostly grade 1-2). Seven of 20 patients (35%) achieved stable disease (SD) >5 months or complete/partial (CR/PR) responses (duration = 5.6, 5.7, 8, 2 +, 18+, 15, 22+ months). Tumor regression of over 20% (100%, 100%, 27%, 23%, 23%) occurred in 5/17 (29%) EWS patients with time to treatment failure lasting 22, 2+, 15, 18 and 8 months, respectively. Biopsy samples of one patient taken at the time of emergence of resistance to a different IGF-1R inhibitor, demonstrated upregulation of mTOR pathway proteins, as determined by morphoproteomic analysis of the resistant tumor; and this particular patient achieved a CR with a time to treatment failure of 22 months on our trial. A second patient with EWS had a PR with prior IGF-1R treatment and then had a mixed response with remarkable regression in three lung modules after instituting cixutumumab and temsirolimus, but progression in a fourth lesion. Morphoproteomic analysis of this patient's resistant tumor demonstrated upregulation of mTOR and ERK/MEK signals. The latter suggests the possibility that a combination of IGFR/mTOR and MEK inhibitors might warrant investigation in order to reverse resistance. Four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which was controlled while maintaining drug dose. Side effects of this regimen were well controlled with medication and the assistance of an endocrinologist, when necessary Conclusions: This mechanism-based approach shows evidence of activity for temsirolimus and cixutumumab in EWS family tumors. The majority of best responders developed grade 3 side effects which were well controlled by supportive measures, suggesting that drug dose should not be compromised. This study was supported by R21CA13763301A1 (Aung Naing), U01CA62461 (Razelle Kurzrock), and U01CA62487 (Patricia LoRusso) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-124. doi:1538-7445.AM2012-LB-124
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