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Investigational New Drugs

, Volume 31, Issue 5, pp 1201–1206 | Cite as

Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies

  • Shaji K. Kumar
  • James Jett
  • Randolph Marks
  • Ronald Richardson
  • Fernando Quevedo
  • Timothy Moynihan
  • Gary Croghan
  • Svetomir N. Markovic
  • Keith C. Bible
  • Rui Qin
  • Angelina Tan
  • Julian Molina
  • Scott H. Kaufmann
  • Charles Erlichman
  • Alex A. Adjei
PHASE I STUDIES

Summary

Background. Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models. Methods. This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles. Results. Fourteen patients (7 males, median age 65, range 24–74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m2, establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease. Conclusions. The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m2 on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.

Keywords

Phase 1 trial Sorafenib Bortezomib 

Notes

Acknowledgments

We are indebted to patients participating in this trial and to the enrolling investigators for their interest in and dedication to this study. We also thank the clinical research associates and research protocol specialists at the Mayo Clinic Cancer Center for commitment to the completion of this trial and for administrative assistance.

Funding

This work was supported by National Cancer Institute; CA69912.

Clinicaltrials.gov identifier: NCT00303797

Conflict of Interest

SKK has research funding for clinical trials from Millennium Pharmaceuticals and Onyx Pharmaceuticals, and has participated in advisory boards with Millennium Pharmaceuticals and Onyx Pharmaceuticals.

References

  1. 1.
    Lowinger TB, Riedl B, Dumas J, Smith RA (2002) Design and discovery of small molecules targeting raf-1 kinase. Curr Pharm Des 8(25):2269–2278PubMedCrossRefGoogle Scholar
  2. 2.
    Lyons JF, Wilhelm S, Hibner B, Bollag G (2001) Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer 8(3):219–225PubMedCrossRefGoogle Scholar
  3. 3.
    Bollag G, Freeman S, Lyons JF, Post LE (2003) Raf pathway inhibitors in oncology. Curr Opin Investig Drugs 4(12):1436–1441PubMedGoogle Scholar
  4. 4.
    Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–2622PubMedGoogle Scholar
  5. 5.
    LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi NC, Anderson KC (2002) Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62(17):4996–5000PubMedGoogle Scholar
  6. 6.
    Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61(9):3535–3540PubMedGoogle Scholar
  7. 7.
    Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J (1999) The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5(9):2638–2645PubMedGoogle Scholar
  8. 8.
    Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277(19):16639–16647PubMedCrossRefGoogle Scholar
  9. 9.
    Yu C, Friday BB, Lai JP, Yang L, Sarkaria J, Kay NE, Carter CA, Roberts LR, Kaufmann SH, Adjei AA (2006) Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther 5(9):2378–2387. doi: 10.1158/1535-7163.MCT-06-0235 PubMedCrossRefGoogle Scholar
  10. 10.
    Chen KF, Yu HC, Liu TH, Lee SS, Chen PJ, Cheng AL (2009) Synergistic interactions between sorafenib and bortezomib in hepatocellular carcinoma involve PP2A-dependent Akt inactivation. J Hepatol. doi: 10.1016/j.jhep.2009.10.011 Google Scholar
  11. 11.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134. doi: 10.1056/NEJMoa060655 PubMedCrossRefGoogle Scholar
  12. 12.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390. doi: 10.1056/NEJMoa0708857 PubMedCrossRefGoogle Scholar
  13. 13.
    Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA, O’Connor OA, Shi H, Boral AL, Goy A (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24(30):4867–4874. doi: 10.1200/JCO.2006.07.9665 PubMedCrossRefGoogle Scholar
  14. 14.
    Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498. doi: 10.1056/NEJMoa043445 PubMedCrossRefGoogle Scholar
  15. 15.
    Bellmunt J, Eisen T, Fishman M, Quinn D (2010) Experience with sorafenib and adverse event management. Crit Rev Oncol Hematol. doi: 10.1016/j.critrevonc.2010.03.006 PubMedGoogle Scholar
  16. 16.
    Kobayashi Y, Kanemitu T, Kamoto A, Satoh M, Mori N, Sekii K, Yoshioka T, Itatani H, Fujimoto T (2010) Painless acute pancreatitis associated with sorafenib treatment: a case report. Med Oncol. doi: 10.1007/s12032-010-9479-2 Google Scholar
  17. 17.
    Minami H, Kawada K, Ebi H, Kitagawa K, Kim YI, Araki K, Mukai H, Tahara M, Nakajima H, Nakajima K (2008) Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. Cancer Sci 99(7):1492–1498. doi: 10.1111/j.1349-7006.2008.00837.x PubMedCrossRefGoogle Scholar
  18. 18.
    Li M, Srinivas S (2007) Acute pancreatitis associated with sorafenib. South Med J 100(9):909–911PubMedCrossRefGoogle Scholar
  19. 19.
    Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, Liang C, Booth B, Chidambaram N, Morse D, Sridhara R, Garvey P, Justice R, Pazdur R (2006) Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 12(24):7271–7278. doi: 10.1158/1078-0432.CCR-06-1249 PubMedCrossRefGoogle Scholar
  20. 20.
    Elouni B, Ben Salem C, Zamy M, Sakhri J, Bouraoui K, Biour M (2010) Bortezomib-induced acute pancreatitis. JOP 11(3):275–276PubMedGoogle Scholar
  21. 21.
    Laber DA, Mushtaq M (2009) Compassionate use of sorafenib in patients with advanced renal cell cancer. Clin Genitourin Cancer 7(1):34–38. doi: 10.3816/CGC.2009.n.006 PubMedCrossRefGoogle Scholar
  22. 22.
    Ng R, Chen EX (2006) Sorafenib (BAY 43–9006): review of clinical development. Curr Clin Pharmacol 1(3):223–228PubMedCrossRefGoogle Scholar
  23. 23.
    Kondagunta GV, Drucker B, Schwartz L, Bacik J, Marion S, Russo P, Mazumdar M, Motzer RJ (2004) Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol 22(18):3720–3725. doi: 10.1200/JCO.2004.10.155 PubMedCrossRefGoogle Scholar
  24. 24.
    Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T, Lathia C, Petrenciuc O, Moore MJ (2006) Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 12(1):144–151. doi: 10.1158/1078-0432.CCR-05-1571 PubMedCrossRefGoogle Scholar
  25. 25.
    Blumenschein GR Jr, Gatzemeier U, Fossella F, Stewart DJ, Cupit L, Cihon F, O’Leary J, Reck M (2009) Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. J Clin Oncol 27(26):4274–4280. doi: 10.1200/JCO.2009.22.0541 PubMedCrossRefGoogle Scholar
  26. 26.
    Butler C, Butler WM, Rizvi AA (2009) Sustained remission with the kinase inhibitor sorafenib in Stage IV metastatic adrenocortical carcinoma. Endocr Pract:1–19. doi: 10.4158/EP09295.CR
  27. 27.
    Lara PN Jr, Chansky K, Davies AM, Franklin WA, Gumerlock PH, Guaglianone PP, Atkins JN, Farneth N, Mack PC, Crowley JJ, Gandara DR (2006) Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (S0327). J Thorac Oncol 1(9):996–1001PubMedCrossRefGoogle Scholar
  28. 28.
    Scagliotti GV, Germonpre P, Bosquee L, Vansteenkiste J, Gervais R, Planchard D, Reck M, De Marinis F, Lee JS, Park K, Biesma B, Gans S, Ramlau R, Szczesna A, Makhson A, Manikhas G, Morgan B, Zhu Y, Chan KC, von Pawel J (2010) A randomized phase II study of bortezomib and pemetrexed, in combination or alone, in patients with previously treated advanced non-small-cell lung cancer. Lung Cancer 68(3):420–426. doi: 10.1016/j.lungcan.2009.07.011 PubMedCrossRefGoogle Scholar
  29. 29.
    Ramakrishnan V, Timm M, Haug JL, Kimlinger TK, Wellik LE, Witzig TE, Rajkumar SV, Adjei AA, Kumar S (2010) Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene 29(8):1190–1202. doi: 10.1038/onc.2009.403 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Shaji K. Kumar
    • 1
    • 5
  • James Jett
    • 2
  • Randolph Marks
    • 2
  • Ronald Richardson
    • 2
  • Fernando Quevedo
    • 2
  • Timothy Moynihan
    • 2
  • Gary Croghan
    • 2
  • Svetomir N. Markovic
    • 1
    • 2
  • Keith C. Bible
    • 2
  • Rui Qin
    • 3
  • Angelina Tan
    • 2
    • 3
  • Julian Molina
    • 2
  • Scott H. Kaufmann
    • 1
  • Charles Erlichman
    • 2
  • Alex A. Adjei
    • 4
  1. 1.Divisions of Hematology and Internal MedicineMayo ClinicRochesterUSA
  2. 2.Division of Medical Oncology and Department of OncologyMayo ClinicRochesterUSA
  3. 3.Division of Biostatistical Statistics and InformaticsMayo ClinicRochesterUSA
  4. 4.Department of MedicineRoswell Park Cancer InstituteBuffaloUSA
  5. 5.Division of HematologyMayo ClinicRochesterUSA

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