Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
British Journal of Cancer (Impact Factor: 4.84). 03/2013; 108(4):826-30. DOI: 10.1038/bjc.2013.46
Source: PubMed


Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy without an available effective systemic chemotherapy. Insulin growth factor 2 (IGF-2) overexpression leading to the activation of the IGF-1 receptor (IGF-1R)/mammalian target of rapamycin (mTOR) pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at IGF-1R was combined with temsirolimus on the basis of preclinical data.

Patients received cixutumumab, 3–6 mg kg−1 intravenously (IV) weekly, and temsirolimus, 25–37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks.

Twenty-six patients were enrolled (13 (50%) men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug related, were grade 1–2 thrombocytopenia (38%), mucositis (58%), hypercholesterolaemia (31%), hypertriglyceridemia (35%), and hyperglycaemia (31%). In all, 11 of 26 patients (42%) achieved stable disease (SD) >6 months (duration range=6–21 months) with 3 of the 11 having received a prior IGF-1R inhibitor.

Cixutumumab combined with temsirolimus was well tolerated and >40% of patients achieved prolonged SD.

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Available from: David S Hong, Oct 17, 2014
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    • "Recently , a phase 2 study used a IMCA12 ( cixutumab ) , a fully humanized IGF - 1R antibody showed a lack of efficacy in a cohort of 19 patients ( Lerario et al . , 2014 ) . In another study , the association of cituximab with temsirolomus , an inhibitor of mammalian targets of IGF - 1R signaling , led to a stable disease in 42% of the patients ( Naing et al . , 2013 ) ."
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    ABSTRACT: Adrenocortical carticnoma (ACC) is a rare malignancy with an incidence of 0.7-2.0 cases/million habitants/year. The diagnosis of malignancy relies on careful investigations of clinical, biological, and imaging features before surgery and pathological examination after tumor removal. Most patients present with steroid hormone excess or abdominal mass effects, but 15% of patients with ACC is initially diagnosed incidentally. After the diagnosis, in order to assess the ACC prognosis and establish an adequate basis for treatment decisions different tools are proposed. The stage classification proposed by the European Network for the Study of Adrenal Tumors (ENSAT) is recommended. Pathology reports define the Weiss score, the resection status and the proliferative index, including the mitotic count and the Ki67 index. As far as the treatment is concerned, in case of tumor limited to the adrenal gland, the complete resection of the tumor is the first option. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Recently, the First International Randomized (FIRM-ACT) Trial in metastatic ACC reported the association between mitotane and etoposide/doxorubicin/cisplatin (EDP) as the new standard in first line treatment of ACC. In last years, new targeted therapies, including the IGF-1 receptor inhibitors, have been investigated, but their efficacy remains limited. Thus, new treatment concepts are urgently needed. The ongoing "omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully will lead to better therapies.
    Frontiers in Cell and Developmental Biology 07/2015; 3:45. DOI:10.3389/fcell.2015.00045
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    • "Stable disease was observed in 42% of these patients (Naing, Lorusso et al. 2013). "
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    • "An exploratory study of the use of everolimus, a rapamycin analog, has shown no clinical response.70 Combination treatment targeting mTOR showed more promise in a recent phase-I trial using the IGF-1R antibody cixutumumab combined with temsirolimus, where 42% of patients achieved stable disease for a minimum of 6 months.71 "
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    ABSTRACT: Adrenal cortical carcinoma (ACC) is a rare cancer that poses a number of management challenges due to the limited number of effective systemic treatments. Complete surgical resection offers the best chance of long-term survival. However, despite complete resection, ACC is associated with high recurrence rates. This review will discuss the management of recurrent ACC in adults following complete surgical resection. Management should take place in a specialist center and treatment decisions must consider the individual tumor biology of each case of recurrence. Given the fact that ACC commonly recurs, management to prevent recurrence should be considered from initial diagnosis with the use of adjuvant mitotane. Close follow up with clinical examination and imaging is important for early detection of recurrent disease. Locoregional recurrence may be isolated, and repeat surgical resection should be considered along with mitotane. The use of radiotherapy in ACC remains controversial. Systemic recurrence most often involves liver, pulmonary, and bone metastasis and is usually managed with mitotane, with or without combination chemotherapy. There is a limited role for surgical resection in systemic recurrence in selected patients. In all patients with recurrent disease, control of excessive hormone production is an important part of management. Despite intensive management of recurrent ACC, treatment failure is common and the use of clinical trials and novel treatment is an important part of management.
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