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A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies

  • PHASE I STUDIES
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Summary

Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1–14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m2). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m2 to 1.5 mg/m2. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m2. DLTs consisted of grade 3 fatigue in three patients (1 mg/m2,1.3 mg/m2 and 1.5 mg/m2) and grade 3 hyponatremia in one patient (1.5 mg/m2). The most common grade 1/2 toxicities included nausea (60.9 %), fatigue (34.8 %), diaphoresis (34.8 %), anorexia (30.4 %) and constipation (26.1 %). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle.

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References

  1. Workman JL, Kingston RE (1998) Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu Rev Biochem 67:545–579

    Article  CAS  PubMed  Google Scholar 

  2. Arts J, de Schepper S, Van Emelen K (2003) Histone deacetylase inhibitors: from chromatin remodeling to experimental cancer therapeutics. Curr Med Chem 10:2343–2350

    Article  CAS  PubMed  Google Scholar 

  3. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  CAS  PubMed  Google Scholar 

  4. Amin HM, Saeed S, Alkan S (2001) Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17). Br J Haematol 115:287–297

    Article  CAS  PubMed  Google Scholar 

  5. Mitsiades N, Mitsiades CS, Richardson PG et al (2003) Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101:4055–4062

    Article  CAS  PubMed  Google Scholar 

  6. Mitsiades CS, Mitsiades NS, McMullan CJ et al (2004) Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A 101:540–545

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K (2003) Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 101:3236–3239

    Article  CAS  PubMed  Google Scholar 

  8. Xu Y, Voelter-Mahlknecht S, Mahlknecht U (2005) The histone deacetylase inhibitor suberoylanilide hydroxamic acid down-regulates expression levels of Bcr-abl, c-Myc and HDAC3 in chronic myeloid leukemia cell lines. Int J Mol Med 15:169–172

    CAS  PubMed  Google Scholar 

  9. Yu C, Rahmani M, Almenara J et al (2003) Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells. Cancer Res 63:2118–2126

    CAS  PubMed  Google Scholar 

  10. Mitsiades CS, Mitsiades N, Richardson PG, Treon SP, Anderson KC (2003) Novel biologically based therapies for Waldenstrom’s macroglobulinemia. Semin Oncol 30:309–312

    Article  CAS  PubMed  Google Scholar 

  11. Zhang C, Richon V, Ni X, Talpur R, Duvic M (2005) Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Invest Dermatol 125:1045–1052

    Article  CAS  PubMed  Google Scholar 

  12. Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 97:10014–10019

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Huang L, Pardee AB (2000) Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Mol Med 6:849–866

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM (2001) The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res 61:8492–8497

    CAS  PubMed  Google Scholar 

  15. Butler LM, Agus DB, Scher HI et al (2000) Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60:5165–5170

    CAS  PubMed  Google Scholar 

  16. Gillenwater AM, Zhong M, Lotan R (2007) Histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis through both mitochondrial and Fas (Cd95) signaling in head and neck squamous carcinoma cells. Mol Cancer Ther 6:2967–2975

    Article  CAS  PubMed  Google Scholar 

  17. Peart MJ, Tainton KM, Ruefli AA et al (2003) Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res 63:4460–4471

    CAS  PubMed  Google Scholar 

  18. Marks PA, Xu WS (2009) Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem 107:600–608

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Rajkumar SV, Richardson PG, Hideshima T, Anderson KC (2005) Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 23:630–639

    Article  CAS  PubMed  Google Scholar 

  20. Nawrocki ST, Carew JS, Pino MS et al (2006) Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 66:3773–3781

    Article  CAS  PubMed  Google Scholar 

  21. Garcia-Mata R, Gao YS, Sztul E (2002) Hassles with taking out the garbage: aggravating aggresomes. Traffic 3:388–396

    Article  CAS  PubMed  Google Scholar 

  22. Yang H, Zonder JA, Dou QP (2009) Clinical development of novel proteasome inhibitors for cancer treatment. Expert Opin Investig Drugs 18:957–971

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Davies AM, Lara PN Jr, Mack PC, Gandara DR (2007) Incorporating bortezomib into the treatment of lung cancer. Clin Cancer Res 13:s4647–s4651

    Article  PubMed  Google Scholar 

  24. Kondagunta GV, Drucker B, Schwartz L et al (2004) Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol 22:3720–3725

    Article  CAS  PubMed  Google Scholar 

  25. Giuliano M, Lauricella M, Calvaruso G et al (1999) The apoptotic effects and synergistic interaction of sodium butyrate and MG132 in human retinoblastoma Y79 cells. Cancer Res 59:5586–5595

    CAS  PubMed  Google Scholar 

  26. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 102:3765–3774

    Article  CAS  PubMed  Google Scholar 

  27. Shah JJ, Orlowski RZ (2009) Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 23(11):1964–1979

    Google Scholar 

  28. Place RF, Noonan EJ, Giardina C (2005) HDACs and the senescent phenotype of WI-38 cells. BMC Cell Biol 6:37

    Article  PubMed Central  PubMed  Google Scholar 

  29. Emanuele S, Lauricella M, Carlisi D et al (2007) SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. Apoptosis 12:1327–1338

    Article  CAS  PubMed  Google Scholar 

  30. Carew JS, Medina EC, Esquivel JA 2nd et al (2010) Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J Cell Mol Med 14(10):2448–2459

    Google Scholar 

  31. Place RF, Noonan EJ, Giardina C (2005) HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha. Biochem Pharmacol 70:394–406

    Article  CAS  PubMed  Google Scholar 

  32. Parise RA, Holleran JL, Beumer JH, Ramalingam S, Egoran MJ (2006) A liquid chromatography-electrospray ionization tandem mass spectrometric assay for quantitation of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamicacid, SAHA) and its metabolites in human serum. J Chromatogr B Anal Technol Biomed Life Sci 840(2):108–115

    Article  CAS  Google Scholar 

  33. Siegel D, Hussein M, Belani C et al (2009) Vorinostat in solid and hematologic malignancies. J Hematol Oncol 2:31

    Article  PubMed Central  PubMed  Google Scholar 

  34. Tsukamoto S, Yokosawa H (2009) Targeting the proteasome pathway. Expert Opin Ther Targets 13:605–621

    Article  CAS  PubMed  Google Scholar 

  35. Maki RG, Kraft AS, Scheu K et al (2005) A multicenter Phase II study of bortezomib in recurrent or metastatic sarcomas. Cancer 103:1431–1438

    Article  CAS  PubMed  Google Scholar 

  36. Traynor AM, Dubey S, Eickhoff JC et al (2009) Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol 4:522–526

    Article  PubMed Central  PubMed  Google Scholar 

  37. Ramalingam SS, Parise RA, Ramanathan RK et al (2007) Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 13:3605–3610

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the University of Wisconsin Carbone Cancer Center (UWCCC) Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics for acquisition of pharmacokinetic data for this research. We also thank the patients who participated in this clinical trial, and the nurses and research specialist of the UWCCC Phase I Program for their efforts in conducting and managing this trial.

Disclosures

T. Hoang received research support from Merck and Millennium Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors.

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Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, K6/568 CSC, Madison, WI, 53792, USA

    William R. Schelman, Anne M. Traynor, Kyle D. Holen, Jill M. Kolesar, Steven Attia, Tien Hoang, Jens Eickhoff, Zhisheng Jiang, Dona Alberti, Rebecca Marnocha, George Wilding & Howard H. Bailey

  2. Clinical Treatment Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Igor Espinoza-Delgado & John J. Wright

  3. Mayo Clinic Cancer Center, Rochester, MN, USA

    Joel M. Reid, Matthew M. Ames & Renee M. McGovern

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  1. William R. Schelman
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  2. Anne M. Traynor
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  3. Kyle D. Holen
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Corresponding author

Correspondence to William R. Schelman.

Additional information

Grant support

UO1 CA062491, Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis, NCI; CTEP Translational Research Initiative, Contract; 1UL 1RR025011, Clinical and Translational Science Award, National Center for Research Resources, NIH; U01 CA69912, Phase I Trials of Anticancer Agents (Mayo Clinic); and 23XS026, CTEP Translational Research Initiative—Support Subcontracts, Correlative Studies Core Laboratory for SAHA Phase I and Phase II Clinical Protocols (Mayo Clinic), SAIC-FREDERICK, INC.

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Schelman, W.R., Traynor, A.M., Holen, K.D. et al. A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies. Invest New Drugs 31, 1539–1546 (2013). https://doi.org/10.1007/s10637-013-0029-6

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  • DOI: https://doi.org/10.1007/s10637-013-0029-6

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