Authors: Cynthia X Ma Vera J Suman Matthew Goetz Paul Haluska Timothy Moynihan Rita Nanda Olufunmilayo Olopade Timothy Pluard Zhanfang Guo Helen X Chen Charles Erlichman Matthew J Ellis Gini F Fleming
Publish Date: 2013/04/19
Volume: 139, Issue: 1, Pages: 145-153
Abstract
The mammalian target of rapamycin mTOR plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer In preclinical studies the antitumor activity of mTOR inhibitors is attenuated by feedback upregulation of AKT mediated in part by Insulinlike growth factor type 1 receptor IGF1R We designed a phase I trial to determine the maximumtolerated dose MTD and pharmacodynamic effects of the IGF1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies A 3 + 3 Phase I design was chosen Temsirolimus and Cixutumumab were administered intravenously on days 1 8 15 and 22 of a 4week cycle Of the 26 patients enrolled four did not complete cycle 1 because of disease progression n = 3 or comorbid condition n = 1 and were replaced The MTD was determined from the remaining 22 patients aged 34–72 median 48 years Most patients 86 had estrogen receptor positive cancer The median number of prior chemotherapy regimens for metastatic disease was 3 The MTD was determined to be Cixutumumab 4 mg/kg and temsirolimus 15 mg weekly Doselimiting toxicities DLTs included mucositis neutropenia and thrombocytopenia Other adverse events included grade 1/2 fatigue anemia and hyperglycemia No objective responses were observed but four patients experienced stable disease that lasted for at least 4 months Compared with baseline there was a significant increase in the serum levels of IGF1 p 0001 and IGFBP3 p = 0019 on day 2 Compared with day 2 there were significant increases in the serum levels of IGF1 p 0001 IGF2 p = 0001 and IGFBP3 p = 0019 on day 8 A phase II study in women with metastatic breast cancer is ongoingWe wish to thank the patients and their families for participation in this study We also thank the nurses clinical research and regulatory coordinators at Washington University Siteman Cancer Center Mayo Clinic Rochester and University of Chicago This trial was partly supported by a Career Development Award from the American Society of Clinical Oncology CXM St Louis Komen Foundation CXM N01CM62205 and N01CM201100071
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