Advertisement

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

Abstract

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.

Keywords

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.

Notes

Acknowledgments

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.

References

  1. 1.
    Abou-Alfa GK, Capanu M, O’Reilly EM, Ma J, Chou JF, Gansukh B, Shia J et al (2013) A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma. J Hepatol. doi: 10.1016/j.jhep.2013.09.008 PubMedGoogle Scholar
  2. 2.
    Almeida MQ, Fragoso MC, Lotfi CF, Santos MG, Nishi MY, Costa MH, Lerario AM et al (2008) Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 93(9):3524–3531. doi: 10.1210/jc.2008-0065 PubMedCrossRefGoogle Scholar
  3. 3.
    Attias-Geva Z, Bentov I, Ludwig DL, Fishman A, Bruchim I, Werner H (2011) Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells. Eur J Cancer 47(11):1717–1726. doi: 10.1016/j.ejca.2011.02.019 PubMedCrossRefGoogle Scholar
  4. 4.
    Barlaskar FM, Spalding AC, Heaton JH, Kuick R, Kim AC, Thomas DG, Giordano TJ, Ben-Josef E, Hammer GD (2009) Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab 94(1):204–212. doi: 10.1210/jc.2008-1456 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30(6):586–623. doi: 10.1210/er.2008-0047 PubMedCrossRefGoogle Scholar
  6. 6.
    Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R et al (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63(24):8912–8921PubMedGoogle Scholar
  7. 7.
    Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE, Tengowski MW et al (2005) Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 11(5):2063–2073. doi: 10.1158/1078-0432.CCR-04-1070 PubMedCrossRefGoogle Scholar
  8. 8.
    Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, Terzolo M et al (2009) Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 115(2):243–250. doi: 10.1002/cncr.24030 PubMedCrossRefGoogle Scholar
  9. 9.
    Fassnacht M, Kroiss M, Allolio B (2013) Update in adrenocortical carcinoma. J Clin Endocrinol Metab 98(12):4551–4564. doi: 10.1210/jc.2013-3020 PubMedCrossRefGoogle Scholar
  10. 10.
    Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S et al (2012) Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 366(23):2189–2197. doi: 10.1056/NEJMoa1200966 PubMedCrossRefGoogle Scholar
  11. 11.
    Fottner C, Hoeflich A, Wolf E, Weber MM (2004) Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis. Horm Metab Res 36(6):397–405. doi: 10.1055/s-2004-814563 PubMedCrossRefGoogle Scholar
  12. 12.
    Furstenberger G, Senn HJ (2002) Insulin-like growth factors and cancer. Lancet Oncol 3(5):298–302PubMedCrossRefGoogle Scholar
  13. 13.
    Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J, Sanders D, Thomas DG, Doherty G, Hammer G (2009) Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res 15(2):668–676. doi: 10.1158/1078-0432.CCR-08-1067 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW (2009) Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab 94(6):1853–1878. doi: 10.1210/jc.2008-2291 PubMedCrossRefGoogle Scholar
  15. 15.
    Haluska P, Worden F, Olmos D, Yin D, Schteingart D, Batzel GN, Paccagnella ML, de Bono JS, Gualberto A, Hammer GD (2010) Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 65(4):765–773. doi: 10.1007/s00280-009-1083-9 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Heaton JH, Wood MA, Kim AC, Lima LO, Barlaskar FM, Almeida MQ, Fragoso MC et al (2012) Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and beta-catenin. Am J Pathol 181(3):1017–1033. doi: 10.1016/j.ajpath.2012.05.026 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF, Proye C (2001) Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 25(7):891–897PubMedCrossRefGoogle Scholar
  18. 18.
    Kurmasheva RT, Dudkin L, Billups C, Debelenko LV, Morton CL, Houghton PJ (2009) The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res 69(19):7662–7671. doi: 10.1158/0008-5472.CAN-09-1693 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Ma CX, Suman VJ, Goetz M, Haluska P, Moynihan T, Nanda R, Olopade O et al (2013) 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(1):145–153. doi: 10.1007/s10549-013-2528-8 PubMedCrossRefGoogle Scholar
  20. 20.
    Naing A, Lorusso P, Fu S, Hong D, Chen HX, Doyle LA, Phan AT, Habra MA, Kurzrock R (2013) Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma. Br J Cancer 108(4):826–830. doi: 10.1038/bjc.2013.46 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Olmos D, Postel-Vinay S, Molife LR, Okuno SH, Schuetze SM, Paccagnella ML, Batzel GN et al (2010) Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing’s sarcoma: a phase 1 expansion cohort study. Lancet Oncol 11(2):129–135. doi: 10.1016/S1470-2045(09)70354-7 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele KP, Chawla SP, Toner GC et al (2011) R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research Through Collaboration study. J Clin Oncol 29(34):4541–4547. doi: 10.1200/JCO.2010.34.0000 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Phan AT (2007) Adrenal cortical carcinoma—review of current knowledge and treatment practices. Hematol Oncol Clin North Am 21(3):489–507. doi: 10.1016/j.hoc.2007.04.007, viii–ixPubMedCrossRefGoogle Scholar
  24. 24.
    Riesterer O, Yang Q, Raju U, Torres M, Molkentine D, Patel N, Valdecanas D, Milas L, Ang KK (2011) Combination of anti-IGF-1R antibody A12 and ionizing radiation in upper respiratory tract cancers. Int J Radiat Oncol Biol Phys 79(4):1179–1187. doi: 10.1016/j.ijrobp.2010.10.003 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Rodon J, DeSantos V, Ferry RJ Jr, Kurzrock R (2008) Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials. Mol Cancer Ther 7(9):2575–2588. doi: 10.1158/1535-7163.MCT-08-0265 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Scagliotti GV, Novello S (2012) The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat Rev 38(4):292–302. doi: 10.1016/j.ctrv.2011.07.008 PubMedCrossRefGoogle Scholar
  27. 27.
    Shin DH, Min HY, El-Naggar AK, Lippman SM, Glisson B, Lee HY (2011) Akt/mTOR counteract the antitumor activities of cixutumumab, an anti-insulin-like growth factor I receptor monoclonal antibody. Mol Cancer Ther 10(12):2437–2448. doi: 10.1158/1535-7163.MCT-11-0235 PubMedCentralPubMedCrossRefGoogle Scholar

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

Personalised recommendations