A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer

• DOI: 10.1007/s10549-013-2528-8
• Publication Date: 2013-04-18T04:33:58Z
• 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
• Keywords: Adult; Sirolimus; Maximum Tolerated Dose; Antibodies, Monoclonal; Breast Neoplasms; Middle Aged; Antibodies, Monoclonal, Humanized; Receptor, IGF Type 1; 3. Good health; 03 medical and health sciences; Insulin-Like Growth Factor Binding Protein 3; 0302 clinical medicine; Insulin-Like Growth Factor II; Antineoplastic Combined Chemotherapy Protocols; Humans; Female; Insulin-Like Growth Factor I; Neoplasm Metastasis; Aged

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 up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose (MTD) and pharmacodynamic effects of the IGF-1R 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 4-week 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. Dose-limiting 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 IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.