Investigational New Drugs

, Volume 30, Issue 5, pp 2001–2007 | Cite as

Feasibility study of intra-patient sorafenib dose-escalation or re-escalation in patients with previously treated advanced solid tumors

  • Thomas J. Semrad
  • Courtney Eddings
  • Chong-Xian Pan
  • Derick H. Lau
  • David Gandara
  • Laurel Beckett
  • Primo N. LaraJr
PHASE II STUDIES

Summary

Purpose To determine if intra-patient dose escalation of the multi-targeted kinase inhibitor sorafenib is feasible in patients with advanced pretreated solid malignancies. Methods An intra-patient dose escalation scheme starting at 400 mg BID was employed in this prospective trial. Doses were escalated to 600 mg BID for the second cycle and to 800 mg BID for the third cycle in the absence of grade 3+ adverse events. In the event of grade 3+ adverse events during cycle 1, doses were reduced to 400 mg daily through cycle 2. Dose re-escalation for cycle 3 was allowed in the absence of grade 3+ adverse events during cycle 2. Further dose escalation was prohibited. The primary endpoint was the overall percentage of patients tolerating dose escalation to 600 mg BID through cycle 2 or tolerating re-escalation to 400 mg BID through cycle 3. Results Fifty eligible patients with various solid tumors and a median of 3 prior therapies were enrolled. Eleven patients (22%) tolerated primary dose escalation or re-escalation. Only 14 patients (28%) completed cycle 1 without dose modification or discontinuing treatment. Seven of 13 patients tolerated primary dose escalation through cycle 2. Four of 5 patients tolerated dose re-escalation through cycle 3. Reasons for escalation failure included tumor progression (42%) and adverse events (26%). Common grade 3+ adverse events included hand-foot skin reaction, hypertension, and hypophosphatemia. Conclusions Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients. Sorafenib dose escalation remains an investigational approach.

Keywords

Dose escalation Dose re-escalation Dose-toxicity relationship Maximum tolerated dose Sorafenib 

Notes

Acknowledgements

Research support provided by Bayer Healthcare/Onyx Pharmaceuticals and UC Davis Cancer Center Support Grant, P30CA093373-06.

Study Identifier

NCT00810394. Presented in part at the 2010 ASCO Annual Meeting (Abstract #3055)

Disclosure

Dr. Lara received research funding from Bayer Healthcare and Onyx Pharmaceuticals for the conduct of this trial. There is no other conflict of interest disclosure.

References

  1. 1.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. doi: 10.1158/0008-5472.CAN-04-1443 PubMedCrossRefGoogle Scholar
  2. 2.
    Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, de Valeriola D, Strumberg D, Brendel E, Haase CG, Schwartz B, Piccart M (2005) Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 92(10):1855–1861. doi: 10.1038/sj.bjc.6602584 PubMedCrossRefGoogle Scholar
  3. 3.
    Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11(15):5472–5480. doi: 10.1158/1078-0432.CCR-04-2658 PubMedCrossRefGoogle Scholar
  4. 4.
    Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O, Cihon F, Lathia C, Schwartz B (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43–9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16(10):1688–1694. doi: 10.1093/annonc/mdi310 PubMedCrossRefGoogle Scholar
  5. 5.
    Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, Faghih M, Brendel E, Voliotis D, Haase CG, Schwartz B, Awada A, Voigtmann R, Scheulen ME, Seeber S (2005) Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol 23(5):965–972. doi: 10.1200/JCO.2005.06.124 PubMedCrossRefGoogle Scholar
  6. 6.
    Strumberg D, Clark JW, Awada A, Moore MJ, Richly H, Hendlisz A, Hirte HW, Eder JP, Lenz HJ, Schwartz B (2007) Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12(4):426–437. doi: 10.1634/theoncologist.12-4-426 PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    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
  9. 9.
    Rini BI (2007) Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res 13(4):1098–1106. doi: 10.1158/1078-0432.CCR-06-1989 PubMedCrossRefGoogle Scholar
  10. 10.
    Flaherty KT, Brose MS (2009) Sorafenib-related hand-foot skin reaction improves, not worsens, with continued treatment. Clin Cancer Res 15(24):7749. doi: 10.1158/1078-0432.CCR-09-1190 PubMedCrossRefGoogle Scholar
  11. 11.
    Amato RJ, Harris P, Dalton M, Khan M, Alter R, Zhai Q, Brady JR, Jac J, Hauke R, Srinivas S (2007) A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol 25 (June 20 suppl):abstr 5026Google Scholar
  12. 12.
    Amato RJ, Jac J, Harris P, Dalton M, Saxena S, Monzon F, Zhai J, Brady JR, Willis JP (2008) A phase II trial of intra-patient dose escalated-sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol 26 (May 20 suppl):abstr 5122Google Scholar
  13. 13.
    Srinivas S, Harshman L, Hauke R (2009) Sorafenib monotherapy in patients with treatment-naive metastatic renal cell cancer: preliminary results of a phase II intra-patient dose-escalation study. J Clin Oncol 27 (suppl):abstr e14564Google Scholar
  14. 14.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRefGoogle Scholar
  15. 15.
    Riechelmann RP, Chin S, Wang L, Tannock IF, Berthold DR, Moore MJ, Knox JJ (2008) Sorafenib for metastatic renal cancer: the Princess Margaret experience. Am J Clin Oncol 31(2):182–187. doi: 10.1097/COC.0b013e3181574084 PubMedCrossRefGoogle Scholar
  16. 16.
    La Vine DB, Coleman TA, Davis CH, Carbonell CE, Davis WB (2010) Frequent dose interruptions are required for patients receiving oral kinase inhibitor therapy for advanced renal cell carcinoma. Am J Clin Oncol 33(3):217–220. doi: 10.1097/COC.0b013e3181a650a6 PubMedGoogle Scholar
  17. 17.
    Miller AA, Murry DJ, Owzar K, Hollis DR, Kennedy EB, Abou-Alfa G, Desai A, Hwang J, Villalona-Calero MA, Dees EC, Lewis LD, Fakih MG, Edelman MJ, Millard F, Frank RC, Hohl RJ, Ratain MJ (2009) Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 27(11):1800–1805. doi: 10.1200/JCO.2008.20.0931 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Thomas J. Semrad
    • 1
    • 2
  • Courtney Eddings
    • 1
  • Chong-Xian Pan
    • 1
    • 2
  • Derick H. Lau
    • 1
    • 2
  • David Gandara
    • 1
  • Laurel Beckett
    • 3
  • Primo N. LaraJr
    • 1
    • 2
  1. 1.Division of Hematology/Oncology, Department of Internal MedicineUniversity of California Davis Cancer CenterSacramentoUSA
  2. 2.Section of Hematology/Oncology, The Department of Veterans Affairs Northern California Health Care SystemSacramentoUSA
  3. 3.Division of Biostatistics, Department of Public Health SciencesUniversity of California, DavisDavisUSA

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