title: A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer.
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 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.
authors.affiliation: Section of Breast Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, P.O. Box 8056, St. Louis, MO 63110, USA. cma@dom.wustl.edu
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Matthew
authors.initials: M
authors.lastname: Goetz
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.forename: Timothy
authors.initials: T
authors.lastname: Moynihan
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.forename: Olufunmilayo
authors.initials: O
authors.lastname: Olopade
authors.forename: Timothy
authors.initials: T
authors.lastname: Pluard
authors.forename: Zhanfang
authors.initials: Z
authors.lastname: Guo
authors.forename: Helen X
authors.initials: HX
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018972:Insulin-Like Growth Factor Binding Protein 3; C557414:cixutumumab; C401859:temsirolimus; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D020123:Sirolimus