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

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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.

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Acknowledgments

We 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 (C.X.M.), St. Louis Komen Foundation (C.X.M.), N01-CM62205, and N01-CM-2011-00071.

Conflict of interest

All authors disclosed no conflict of interest.

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Authors and Affiliations

  1. 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

    Cynthia X. Ma, Timothy Pluard, Zhanfang Guo & Matthew J. Ellis

  2. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

    Cynthia X. Ma, Timothy Pluard & Matthew J. Ellis

  3. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MO, USA

    Vera J. Suman

  4. Department of Oncology, Mayo Clinic, Rochester, MO, USA

    Matthew Goetz, Paul Haluska, Timothy Moynihan & Charles Erlichman

  5. Division of Hematology and Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA

    Rita Nanda, Olufunmilayo Olopade & Gini F. Fleming

  6. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Helen X. Chen

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  1. Cynthia X. Ma
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  2. Vera J. Suman
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  12. Matthew J. Ellis
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  13. Gini F. Fleming
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Correspondence to Cynthia X. Ma.

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Ma, C.X., Suman, V.J., Goetz, M. et al. A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 139, 145–153 (2013). https://doi.org/10.1007/s10549-013-2528-8

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