Investigational New Drugs

, Volume 31, Issue 1, pp 115–125 | Cite as

A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer

  • A. Dasari
  • L. Gore
  • W. A. Messersmith
  • S. Diab
  • A. Jimeno
  • C. D. Weekes
  • K. D. Lewis
  • H. A. Drabkin
  • T. W. Flaig
  • D. R. Camidge
PHASE I STUDIES

Summary

Background This phase I study evaluated the safety, tolerability and preliminary efficacy of sorafenib combined with vorinostat in patients with solid tumors. Patients and methods Patients were treated with sorafenib 400 mg po bid daily and vorinostat 200–400 mg po days 1–14 of a 21 day cycle to establish the recommended phase II dose (RP2D). The tolerability and efficacy of the RP2D was further tested in two cohorts of 6–12 patients each with advanced RCC and NSCLC. Results 17 patients were treated in the dose escalation phase that established the RP2D at sorafenib 400 mg po bid daily, vorinostat 300 mg po days 1–14. Dose limiting toxicities (DLT) included intolerable grade 2 hand-foot syndrome and multiple grade 1 toxicities causing dose interruption for more than 14 days. Despite good tolerance in the all-comers population, the RP2D was poorly tolerated in the RCC and NSCLC cohorts with the majority being unable to finish 2 full cycles of therapy. Although there were no confirmed responses, 1 patient each with NSCLC adenocarcinoma and renal sarcoma had unconfirmed partial responses and 5 of 8 patients with RCC having durable minor responses (11–26 %), including 2 who were on treatment for nearly a year. Conclusions Although tolerable in other tumor types, sorafenib 400 mg po bid with vorinostat 300 mg po daily days 1–14 of a 21-day cycle is not tolerable without dose reductions/delays in RCC and NSCLC patients. These patients may require lower doses than the RP2D explored within this study. No confirmed responses were seen but minor responses particularly in RCC were observed.

Keywords

Phase I SAHA Sorafenib Vorinostat 

Notes

Acknowledgments

We would like to thank Mark Morrow and DeLee Maxson (University of Colorado) for research co-ordination associated with this study.

Grant support

This was an investigator initiated study (PI: D.R. Camidge) supported by Bayer/Onyx and Merck.

Disclosure of potential conflicts of interest

D. R. Camidge: Research Funding Bayer/Onyx and Merck

L. Gore: Unfunded clinical trials (4) from Merck

All other authors: None

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300. doi: 10.3322/caac.20073 PubMedCrossRefGoogle Scholar
  2. 2.
    Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307. doi: 10.1038/nature10144 PubMedCrossRefGoogle Scholar
  3. 3.
    Kaelin WG Jr (2007) The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res: An Official Journal of the American Association for Cancer Research 13(2 Pt 2):680s–684s. doi: 10.1158/1078-0432.CCR-06-1865 CrossRefGoogle Scholar
  4. 4.
    Lee JT, McCubrey JA (2003) BAY-43-9006 Bayer/Onyx. Curr Opin Investig Drugs 4(6):757–763PubMedGoogle Scholar
  5. 5.
    Hotte SJ, Hirte HW (2002) BAY 43-9006: early clinical data in patients with advanced solid malignancies. Curr Pharm Des 8(25):2249–2253PubMedCrossRefGoogle Scholar
  6. 6.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM (2009) Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol: Official Journal of the American Society of Clinical Oncology 27(20):3312–3318. doi: 10.1200/JCO.2008.19.5511 CrossRefGoogle Scholar
  7. 7.
    Korpanty G, Smyth E, Sullivan LA, Brekken RA, Carney DN (2010) Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway. Exp Biol Med (Maywood) 235(1):3–9. doi: 10.1258/ebm.2009.009191 CrossRefGoogle Scholar
  8. 8.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550. doi: 10.1056/NEJMoa061884 PubMedCrossRefGoogle Scholar
  9. 9.
    Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A (2007) Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist 12(2):191–200. doi: 10.1634/theoncologist.12-2-191 PubMedCrossRefGoogle Scholar
  10. 10.
    Kramer BW, Gotz R, Rapp UR (2004) Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure. BMC Cancer 4:24. doi: 10.1186/1471-2407-4-24 PubMedCrossRefGoogle Scholar
  11. 11.
    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: Official Journal of the American Society of Clinical Oncology 27(26):4274–4280. doi: 10.1200/JCO.2009.22.0541 CrossRefGoogle Scholar
  12. 12.
    Takimoto CH, Awada A (2008) Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents: a review of clinical trials. Canc Chemother Pharmacol 61(4):535–548. doi: 10.1007/s00280-007-0639-9 CrossRefGoogle Scholar
  13. 13.
    Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, Ricker JL, Arduino JM, Duvic M (2007) Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol: Official Journal of the American Society of Clinical Oncology 25(21):3109–3115. doi: 10.1200/JCO.2006.10.2434 CrossRefGoogle Scholar
  14. 14.
    Siegel D, Hussein M, Belani C, Robert F, Galanis E, Richon VM, Garcia-Vargas J, Sanz-Rodriguez C, Rizvi S (2009) Vorinostat in solid and hematologic malignancies. J Hematol Oncol 2:31. doi: 10.1186/1756-8722-2-31 PubMedCrossRefGoogle Scholar
  15. 15.
    Kim HJ, Bae SC (2011) Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Translat Res 3(2):166–179Google Scholar
  16. 16.
    Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K (2007) Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. Clin Cancer Res: An Official Journal of the American Association for Cancer Research 13(16):4882–4890. doi: 10.1158/1078-0432.CCR-06-3093 CrossRefGoogle Scholar
  17. 17.
    Dasmahapatra G, Yerram N, Dai Y, Dent P, Grant S (2007) Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 down-regulation. Clin Cancer Res: An Official Journal of the American Association for Cancer Research 13(14):4280–4290. doi: 10.1158/1078-0432.CCR-07-0835 CrossRefGoogle Scholar
  18. 18.
    Zhang G, Park MA, Mitchell C, Hamed H, Rahmani M, Martin AP, Curiel DT, Yacoub A, Graf M, Lee R, Roberts JD, Fisher PB, Grant S, Dent P (2008) Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation. Clin Cancer Res: An Official Journal of the American Association for Cancer Research 14(17):5385–5399. doi: 10.1158/1078-0432.CCR-08-0469 CrossRefGoogle Scholar
  19. 19.
    Park MA, Mitchell C, Zhang G, Yacoub A, Allegood J, Haussinger D, Reinehr R, Larner A, Spiegel S, Fisher PB, Voelkel-Johnson C, Ogretmen B, Grant S, Dent P (2010) Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca(2+)-de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway. Cancer Res 70(15):6313–6324. doi: 10.1158/0008-5472.CAN-10-0999 PubMedCrossRefGoogle Scholar
  20. 20.
    Walker T, Mitchell C, Park MA, Yacoub A, Graf M, Rahmani M, Houghton PJ, Voelkel-Johnson C, Grant S, Dent P (2009) Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms. Mol Pharmacol 76(2):342–355. doi: 10.1124/mol.109.056523 PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    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
  23. 23.
    Tan J, Cang S, Ma Y, Petrillo RL, Liu D (2010) Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol 3:5. doi: 10.1186/1756-8722-3-5 PubMedCrossRefGoogle Scholar
  24. 24.
    Adjei AA, Blumenschein GR Jr, Mandrekar S, Hillman S, Gatzemeier U, Heigener D (2011) Long-term safety and tolerability of sorafenib in patients with advanced non-small-cell lung cancer: a case-based review. Clin Lung Canc 12(4):212–217. doi: 10.1016/j.cllc.2011.03.021 CrossRefGoogle Scholar
  25. 25.
    Gridelli C, Morgillo F, Favaretto A, de Marinis F, Chella A, Cerea G, Mattioli R, Tortora G, Rossi A, Fasano M, Pasello G, Ricciardi S, Maione P, Di Maio M, Ciardiello F (2011) Sorafenib in combination with erlotinib or with gemcitabine in elderly patients with advanced non-small-cell lung cancer: a randomized phase II study. Ann Oncol: Official Journal of the European Society for Medical Oncology / ESMO 22(7):1528–1534. doi: 10.1093/annonc/mdq630 CrossRefGoogle Scholar
  26. 26.
    Feldman M, van der Goot FG (2009) Novel ubiquitin-dependent quality control in the endoplasmic reticulum. Trends Cell Biol 19(8):357–363. doi: 10.1016/j.tcb.2009.05.005 PubMedCrossRefGoogle Scholar
  27. 27.
    Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol: Official Journal of the American Society of Clinical Oncology 22(11):2184–2191. doi: 10.1200/JCO.2004.11.022JCO.2004.11.022] CrossRefGoogle Scholar
  28. 28.
    Wong NS, Seah EZ, Wang LZ, Yeo WL, Yap HL, Chuah B, Lim YW, Ang PC, Tai BC, Lim R, Goh BC, Lee SC (2011) Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. Pharmacogenet Genomics. doi: 10.1097/FPC.0b013e32834a8639
  29. 29.
    Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Abrao Miziara JE, Balint B, De Marinis F, Keller A, Aren O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol: Official Journal of the American Society of Clinical Oncology 28(11):1835–1842. doi: 10.1200/JCO.2009.26.1321 CrossRefGoogle Scholar
  30. 30.
    Wu S, Keresztes RS (2011) Antiangiogenic agents for the treatment of nonsmall cell lung cancer: characterizing the molecular basis for serious adverse events. Canc Investig 29(7):460–471. doi: 10.3109/07357907.2011.597815 Google Scholar
  31. 31.
    Pili RL, Lodge M, Verheul H, Mashtare T, Wahl RL, Martin JE, Espinoza-Delgado I, Liu G, Carducci MA (2010) Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in pre-treated patients with renal cell carcinoma: safety, efficacy and pharmacodynamic results. In: ASCO Genitourinary Cancers Symposium, San Francisco, CA, USA, 5–7 March 2010Google Scholar
  32. 32.
    Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR, Tsao A, Stewart DJ, Hicks ME, Erasmus J, Gupta S, Alden CM, Liu S, Tang X, Khuri FR, Tran HT, Johnson BE, Heymach JV, Mao L, Fossella F, Kies MS, Papadimitrakopoulou V, Davis SE, Lippman SM, Hong WK (2011) The BATTLE trial: personalizing therapy for lung cancer. Canc Discov 1(1):44–53. doi: 10.1158/2159-8274.cd-10-0010 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • A. Dasari
    • 1
    • 4
  • L. Gore
    • 1
    • 2
  • W. A. Messersmith
    • 1
  • S. Diab
    • 1
  • A. Jimeno
    • 1
  • C. D. Weekes
    • 1
  • K. D. Lewis
    • 1
  • H. A. Drabkin
    • 3
  • T. W. Flaig
    • 1
  • D. R. Camidge
    • 1
  1. 1.University of Colorado Cancer CenterAuroraUSA
  2. 2.University of Colorado Denver and Children’s Hospital ColoradoAuroraUSA
  3. 3.Medical University of South CarolinaCharlestonUSA
  4. 4.Department of Gastrointestinal Medical OncologyUniversity of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations