Responders received a median of 18 cycles of treatment (range, 6C46)
Responders received a median of 18 cycles of treatment (range, 6C46). 24 months (IQR 173C369). In the thymoma cohort five (14%) of 37 patients (95% CI 5C29%) achieved a partial response, 28 had stable disease and four had progressive disease. Corresponding numbers for the thymic carcinoma cohort were zero of 12 patients (95% CI 0C26%), five and seven. The most common Cloprostenol (sodium salt) grade 3C4 adverse events in both cohorts combined were hyperglycemia (5 [10%] of 49 patients), lipase elevation (3 [6%]), weight loss, tumor pain, and hyperuricemia (2 each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions (five new-onset) during treatment, the most common Rabbit Polyclonal to GAB2 of which was real red cell aplasia. Two (4%) of 49 treated patients died while on study. One Cloprostenol (sodium salt) case was attributed to disease progression and the other to diseaseCrelated complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Interpretation Cixutumumab monotherapy is usually well tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Funding Division of Cancer Treatment and Diagnosis, National Malignancy Institute/National Institutes of Health and ImClone Systems. Introduction Thymic epithelial tumors (TETs) are rare mediastinal tumors that are associated with relatively slow growth and a reasonably good prognosis.1 The association between a myriad of autoimmune diseases and thymoma is well described. Alterations in cellular and humoral immunity provide an explanation for the development of autoimmune disorders in these patients.2,3 Thymic carcinomas, the most aggressive form of TETs, are usually not associated with autoimmune diseases. 2 TETs are relatively sensitive to chemotherapy.4 However, few effective options exist for the treatment of relapsed or refractory disease. Initial studies of targeted therapy have yielded disappointing results.4 The insulin-like growth factor (IGF) receptor family of tyrosine kinases is expressed in normal and neoplastic tissues.5 Activation of the IGF-1 receptor (IGF-1R) is ligand-dependent and promotes cell proliferation and inhibits apoptosis. Gene amplification and activating mutations of the IGF-1R gene are rare.5 In the thymus, IGF-1 has been shown to increase the thymic epithelial cell populace and influence the development of thymocytes and chemokine expression.6 TETs express IGF-1R, especially in patients with recurrent or advanced disease and aggressive histologic subtypes and IGF-1R expression in primary tumors was associated with worse progression-free survival.7 The clinical benefit of IGF-1R inhibition in TETs was Cloprostenol (sodium salt) first observed in phase 1 studies of monoclonal antibodies targeting the receptor. One patient with metastatic thymoma treated with figitumumab (CP-751,871) at a dose of 20 mg/kg administered once every three weeks had prolonged stable disease lasting for more than one 12 months.8 Another patient with thymoma had disease stabilization lasting greater than 12 weeks in a phase 1 study of cixutumumab (IMC-A12; NSC 742460), which is a fully human, IgG1 monoclonal antibody that binds to IGF-1R with high affinity and induces internalization and degradation of the receptor. In this trial cixutumumab was administered once every two weeks at doses of 6 mg/kg to 15 mg/kg.9 Based on these preclinical and clinical results, we designed this multicentre, open-label, phase 2 Cloprostenol (sodium salt) study to assess the efficacy of cixutumumab at a dose of 20 mg/kg administered intravenously once every three weeks in patients with recurrent TETs. Methods Patients Patients aged 18 years or older with histologically confirmed recurrent TETs who had progressed after at least one platinum-containing chemotherapy regimen with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST; version 11), and adequate organ and bone marrow function were eligible. Further details of eligibility criteria are provided in the supplementary appendix. All patients provided written informed consent prior to enrollment. The study was approved by the National Malignancy Institute and Memorial Sloan Kettering Cancer Center (MSKCC) Institutional Review Boards. Cloprostenol (sodium salt) Procedures Cixutumumab at 20 mg/kg.