Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 5, pp 1241–1246 | Cite as

Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors

  • Jennifer A. Chan
  • Robert J. Mayer
  • Nadine Jackson
  • Paige Malinowski
  • Eileen Regan
  • Matthew H. Kulke
Original Article



Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET.


Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity.


One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand–foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients.


Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use.


Neuroendocrine Phase I Sorafenib Everolimus 



The authors gratefully acknowledge support from the Saul and Gitta Kurlat fund for neuroendocrine tumor research. This work was supported by Novartis, Bayer, and Onyx Pharmaceuticals.

Conflict of interest

  J. Chan: research funding from Novartis, Schering-Plough/Merck, Bayer, and Onyx Pharmaceuticals.


  1. 1.
    Vignot S, Faivre S, Aguirre D et al (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16:525–537PubMedCrossRefGoogle Scholar
  2. 2.
    Yao JC, Shah MH, Ito T et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523PubMedCrossRefGoogle Scholar
  3. 3.
    Pavel ME, Hainsworth JD, Baudin E et al (2011) Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378:2005–2012PubMedCrossRefGoogle Scholar
  4. 4.
    Bowen KA, Silva SR, Johnson JN et al (2009) An analysis of trends and growth factor receptor expression of GI carcinoid tumors. J Gastrointest Surg 13:1773–1780PubMedCrossRefGoogle Scholar
  5. 5.
    Silva SR, Bowen KA, Rychahou PG et al (2011) VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. Int J Cancer 128:1045–1056PubMedCrossRefGoogle Scholar
  6. 6.
    Fjallskog ML, Hessman O, Eriksson B et al (2007) Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas. Acta Oncol 46:741–746PubMedCrossRefGoogle Scholar
  7. 7.
    Fjallskog ML, Lejonklou MH, Oberg KE et al (2003) Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 9:1469–1473PubMedGoogle Scholar
  8. 8.
    Hansel DE, Rahman A, Hermans J et al (2003) Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Mod Pathol 16:652–659PubMedCrossRefGoogle Scholar
  9. 9.
    Raymond E, Dahan L, Raoul JL et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513PubMedCrossRefGoogle Scholar
  10. 10.
    Hobday TJ, Rubin J, Holen K et al. (2007) MC044 h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a Phase II Consortium (P2C) study. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I 25:Abstract 4504Google Scholar
  11. 11.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134PubMedCrossRefGoogle Scholar
  12. 12.
    Mir O, Coriat R, Boudou-Rouquette P et al (2012) Sorafenib-induced diarrhea and hypophosphatemia: mechanisms and therapeutic implications. Ann Oncol 23:280–281PubMedCrossRefGoogle Scholar
  13. 13.
    Molina AM, Feldman DR, Voss MH et al (2012) Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 118:1868–1876PubMedCrossRefGoogle Scholar
  14. 14.
    Harzstark AL, Small EJ, Weinberg VK et al (2011) A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer 117:4194–4200PubMedCrossRefGoogle Scholar
  15. 15.
    Hobday T, Qin R, Reidy D et al. (2012) Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET). J Clin Oncol, 2012 ASCO Annual Meeting Proceedings 30:(suppl 4; abstr 260) Google Scholar
  16. 16.
    Yao J, Phan A, Fogleman D et al (2010) Randomized run-in study of bevacizumab (B) and everolimus (E) in low- to intermediate-grade neuroendocrine tumors (LGNETs) using perfusion CT as functional biomarker. J Clin Oncol, 2010 ASCO Annual Meeting Proceedings 28:15s:(suppl; abstr 4002)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jennifer A. Chan
    • 1
    • 2
  • Robert J. Mayer
    • 1
    • 2
  • Nadine Jackson
    • 1
    • 2
  • Paige Malinowski
    • 1
  • Eileen Regan
    • 1
  • Matthew H. Kulke
    • 1
    • 2
  1. 1.Department of Medical Oncology, Dana-Farber Cancer InstituteBostonUSA
  2. 2.Department of MedicineBrigham and Women’s HospitalBostonUSA

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