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

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

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)145-153
Number of pages9
JournalBreast Cancer Research and Treatment
Volume139
Issue number1
DOIs
StatePublished - May 2013

Keywords

  • Cixutumumab
  • IGF-1R
  • Metastatic breast cancer
  • Temsirolimus
  • mTOR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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