Hormones and Cancer

, Volume 5, Issue 4, pp 232–239 | Cite as

The Combination of Insulin-Like Growth Factor Receptor 1 (IGF1R) Antibody Cixutumumab and Mitotane as a First-Line Therapy for Patients with Recurrent/Metastatic Adrenocortical Carcinoma: a Multi-institutional NCI-Sponsored Trial

  • Antonio M. Lerario
  • Francis P. Worden
  • Carole A. Ramm
  • Elizabeth A. Hasseltine
  • Walter M. Stadler
  • Tobias Else
  • Manisha H. Shah
  • Edem Agamah
  • Krishna Rao
  • Gary D. Hammer
Original Paper


Adrenocortical carcinoma (ACC) is an aggressive malignancy, which lacks an effective systemic treatment. Abnormal activation of insulin-like growth factor receptor 1 (IGF1R) has been frequently observed. Preclinical studies demonstrated that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative effects. A previous phase I trial with an IGF1R inhibitor has demonstrated biological activity against ACC. The objective of this study is to assess the efficacy of the combination of the IGF1R inhibitor cixutumumab (IMC-A12) in association with mitotane as a first-line treatment for advanced/metastatic ACC. We conducted a multicenter, randomized double-arm phase II trial in patients with irresectable recurrent/metastatic ACC. The original protocol included two treatment groups: IMC-A12 + mitotane and mitotane as a single agent, after an initial single-arm phase for safety evaluation with IMC-A12 + mitotane. IMC-A12 was dosed at 10 mg/kg intravenously every 2 weeks. The starting dose for mitotane was 2 g daily, subsequently adjusted according to serum levels/symptoms. The primary endpoint was progression-free survival (PFS) according to RECIST (Response Evaluation Criteria in Solid Tumors). This study was terminated before the randomization phase due to slow accrual and limited efficacy. Twenty patients (13 males, 7 females) with a median age of 50.2 years (range 21.9–79.6) were enrolled for the single-arm phase. Therapeutic effects were observed in 8/20 patients, including one partial response and seven stable diseases. The median PFS was 6 weeks (range 2.66–48). Toxic events included two grade 4 (hyperglycemia and hyponatremia) and one grade 5 (multiorgan failure). Although the regimen demonstrated activity in some patients, the relatively low therapeutic efficacy precluded further studies with this combination of drugs.


Temsirolimus Adrenocortical Carcinoma Mitotane IGF1R Signaling IGF1R Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by the following grants provided by NCI: HHSN261201100070C and HHSN261201100071C.

Conflict of Interest

AML, FPW, CAR, EAH, WMS, MHS, EA, and KR have nothing to disclose. GH is a shareholder of Atterocor, Orphagen, and Embara. He is a consultant for ISIS, Orphagen, Embara, and Atterocor.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Antonio M. Lerario
    • 1
  • Francis P. Worden
    • 2
  • Carole A. Ramm
    • 1
  • Elizabeth A. Hasseltine
    • 1
  • Walter M. Stadler
    • 3
  • Tobias Else
    • 1
  • Manisha H. Shah
    • 4
  • Edem Agamah
    • 5
  • Krishna Rao
    • 6
  • Gary D. Hammer
    • 1
  1. 1.Division of Metabolism, Endocrinology & Diabetes, Medical SchoolUniversity of MichiganAnn ArborUSA
  2. 2.Division of Hematology/OncologyUniversity of MichiganAnn ArborUSA
  3. 3.Division of Hematology/OncologyUniversity of ChicagoChicagoUSA
  4. 4.Ohio State University Comprehensive Cancer CenterColumbusUSA
  5. 5.IHDN—International Health and Development NetworkSpringfieldUSA
  6. 6.Division of Hematology/Medical Oncology, Department of Internal Medicine and Simmons Cancer InstituteSouthern Illinois University School of MedicineSpringfieldUSA

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