Skip to main content

Advertisement

SpringerLink
Log in

A phase I study to determine the pharmacokinetics and urinary excretion of belinostat and metabolites in patients with advanced solid tumors

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Belinostat is an inhibitor of histone deacetylase enzymes, resulting in DNA repair inhibition and apoptosis. Present data are lacking to provide dosing recommendations in renal insufficiency. The purpose of this trial was to assess the pharmacokinetics (PK) of belinostat and belinostat metabolites in plasma and urine.

Methods

This was a phase I, single-center, open-label, two-part study. In Part I, patients received single-agent belinostat 1000 mg/m2. Blood and urine samples were collected at pre-specified time points to determine PK of belinostat and metabolites and their elimination in urine. In Part II, patients were permitted to continue belinostat in 21-day cycles on Days 1 through 5 until disease progression, unacceptable toxicity, or according to patient preference.

Results

A total of nine patients with advanced solid tumors were treated. Median t max for belinostat was observed 10 min after the start of infusion. Concentrations of belinostat rapidly declined with a t 1/2 of 2.9 h. The mean fraction of belinostat excreted unchanged in urine was 0.926 %. The metabolites belinostat glucuronide and 3-ASBA represented the largest fractions of belinostat dose excreted in urine (30.5 and 4.61 %, respectively), while renal excretion appeared to be a minor route of elimination for the parent belinostat (<1 %). The most common adverse events were nausea, fatigue, and diarrhea. One Grade 3 adverse event (constipation) was thought to be treatment related.

Conclusions

Urinary elimination of parent belinostat was minimal, although a combined 36.7 % of belinostat metabolites were excreted in urine. Since these metabolites are primarily inactive, belinostat may not require dosage adjustment in renal dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Sawas A, Radeski D, O’Connor OA (2015) Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review. Ther Adv Hematol 6(4):202–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90(1):85–94

    Article  CAS  PubMed  Google Scholar 

  3. Fraga MF, Ballestar E, Villar-Garea A et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400

    Article  CAS  PubMed  Google Scholar 

  4. Mitsiades N, Mitsiades CS, Richardson PG et al (2003) Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101(10):4055–4062

    Article  CAS  PubMed  Google Scholar 

  5. Poole RM (2014) Belinostat: first global approval. Drugs 74(13):1543–1554

    Article  CAS  PubMed  Google Scholar 

  6. Dai Y, Chen S, Wang L et al (2011) Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF-κB and Bim. Br J Haematol 153(2):222–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Valiuliene G, Stirblyte I, Cicenaite D et al (2015) Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling. J Cell Mol Med 19(7):1742–1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Savickiene J, Treigyte G, Valiuliene G et al (2014) Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells. Anticancer Drugs 25(8):938–949

    Article  CAS  PubMed  Google Scholar 

  9. Buckley MT, Yoon J, Yee H et al (2007) The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo. J Transl Med 5:49

    Article  PubMed  PubMed Central  Google Scholar 

  10. Plumb JA, Finn PW, Williams RJ et al (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2(8):721–728

    CAS  PubMed  Google Scholar 

  11. Dai Y, Chen S, Kramer LB et al (2008) Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res 14(2):549–558

    Article  CAS  PubMed  Google Scholar 

  12. Tumber A, Collins LS, Petersen KD et al (2007) The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Cancer Chemother Pharmacol 60(2):275–283

    Article  CAS  PubMed  Google Scholar 

  13. Na YS, Jung KA, Kim SM et al (2011) The histone deacetylase inhibitor PXD101 increases the efficacy of irinotecan in in vitro and in vivo colon cancer models. Cancer Chemother Pharmacol 68(2):389–398

    Article  CAS  PubMed  Google Scholar 

  14. Duan J, Friedman J, Nottingham L et al (2007) Nuclear factor-kappaB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 6(1):37–50

    Article  CAS  PubMed  Google Scholar 

  15. Spratlin JL, Pitts TM, Kulikowski GN et al (2011) Synergistic activity of histone deacetylase and proteasome inhibition against pancreatic and hepatocellular cancer cell lines. Anticancer Res 31(4):1093–1103

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ma BB, Sung F, Tao Q et al (2010) The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Invest New Drugs 28(2):107–114

    Article  CAS  PubMed  Google Scholar 

  17. Paoluzzi L, Scotto L, Marchi E et al (2010) Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma. Clin Cancer Res 16(2):554–565

    Article  CAS  PubMed  Google Scholar 

  18. Feng R, Oton A, Mapara MY et al (2007) The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. Br J Haematol 139(3):385–397

    Article  CAS  PubMed  Google Scholar 

  19. Sudo M, Chin TM, Mori S et al (2013) Inhibiting proliferation of gefitinib-resistant, non-small cell lung cancer. Cancer Chemother Pharmacol 71(5):1325–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Qian X, LaRochelle WJ, Ara G et al (2006) Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Cancer Ther 5(8):2086–2095

    Article  CAS  PubMed  Google Scholar 

  21. Chien W, Lee DH, Zheng Y et al (2014) Growth inhibition of pancreatic cancer cells by histone deacetylase inhibitor belinostat through suppression of multiple pathways including HIF, NFkB, and mTOR signaling in vitro and in vivo. Mol Carcinog 53(9):722–735

    Article  CAS  PubMed  Google Scholar 

  22. Dovzhanskiy DI, Arnold SM, Hackert T et al (2012) Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer. BMC Cancer 12:226. doi:10.1186/1471-2407-12-226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qian X, Ara G, Mills E et al (2008) Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Cancer 122(6):1400–1410

    Article  CAS  PubMed  Google Scholar 

  24. Gravina GL, Marampon F, Giusti I, Carosa E, Di Sante S, Ricevuto E et al (2012) Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models. Int J Oncol 40(3):711–720

    CAS  PubMed  Google Scholar 

  25. Gravina GL, Marampon F, Muzi P et al (2013) PXD101 potentiates hormonal therapy and prevents the onset of castration-resistant phenotype modulating androgen receptor, HSP90, and CRM1 in preclinical models of prostate cancer. Endocr Relat Cancer 20(3):321–337

    Article  CAS  PubMed  Google Scholar 

  26. Asano T, Sato A, Isono M et al (2015) Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress. Biomed Rep 3(6):797–801

    PubMed  PubMed Central  Google Scholar 

  27. Kim MJ, Lee JS, Park SE et al (2015) Combination treatment of renal cell carcinoma with belinostat and 5-fluorouracil: a role for oxidative stress induced DNA damage and HSP90 regulated thymidine synthase. J Urol 193(5):1660–1668

    Article  CAS  PubMed  Google Scholar 

  28. Chan D, Zheng Y, Tyner JW et al (2013) Belinostat and panobinostat (HDACI): in vitro and in vivo studies in thyroid cancer. J Cancer Res Clin Oncol 139(9):1507–1514

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lin SF, Lin JD, Chou TC et al (2013) Utility of a histone deacetylase inhibitor (PXD101) for thyroid cancer treatment. PLoS One 8(10):e77684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim SH, Kang JG, Kim CS et al (2015) Novel heat shock protein 90 inhibitor NVP-AUY922 synergizes with the histone deacetylase inhibitor PXD101 in induction of death of anaplastic thyroid carcinoma cells. J Clin Endocrinol Metab 100(2):E253–E261

    Article  CAS  PubMed  Google Scholar 

  31. Foss F, Advani R, Duvic M et al (2015) A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol 168(6):811–819

    Article  CAS  PubMed  Google Scholar 

  32. Mackay HJ, Hirte H, Colgan T et al (2010) Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. Eur J Cancer 46(9):1573–1579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. O’Connor OA, Horwitz S, Masszi T et al (2015) Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol 33(23):2492–2499

    Article  PubMed  Google Scholar 

  34. Giaccone G, Rajan A, Berman A et al (2011) Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 29(15):2052–2059

    Article  PubMed  PubMed Central  Google Scholar 

  35. Steele NL, Plumb JA, Vidal L et al (2008) A phase 1 pharmacokinetic and pharmacodynamics study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res 14(3):804–810

    Article  CAS  PubMed  Google Scholar 

  36. Kiesel BF, Parise RA, Tjornelund J et al (2013) LC-MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma. J Pharm Biomed Anal 81–82:89–98

    Article  PubMed  Google Scholar 

  37. Calvo E, Reddy G, Boni V et al (2016) Pharmacokinetics, metabolism, and excretion of 14C-labeled belinostat in patients with recurrent or progressive malignancies. Invest New Drugs 34(2):193–201

    Article  CAS  PubMed  Google Scholar 

  38. Poyet C, Jentsch B, Hermanns T et al (2014) Expression of histone deacetylases 1, 2 and 3 in urothelial bladder cancer. BMC Clin Pathol 14(1):10

    Article  PubMed  PubMed Central  Google Scholar 

  39. Cheung EM, Quinn DI, Tsao–Wei DD et al (2008) Phase II study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced transitional cell urothelial cancer (TCC) after platinum-based therapy: California Cancer Consortium/University of Pittsburgh NCI/CTEP-sponsored trial. J Clin Oncol 26:16058

    Google Scholar 

  40. Hahn NM, Picus J, Bambury RM et al (2015) A phase 2 study of the histone deacetylase (HDAC) inhibitor mocetinostat in patients with urothelial carcinoma (UC) and inactivating alterations of acetyltransferase genes. J Clin Oncol 33(suppl; abstr TPS4575)

  41. Pili R, Quinn D, Hahn NM, et al (2016) A phase I/Ib, open-label, dose-finding study to evaluate safety, pharmacodynamics, and efficacy of pembrolizumab (MK-3475) in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma. J Clin Oncol 34(suppl; abstr TPS4581)

Download references

Acknowledgments

Spectrum Pharmaceuticals, Inc., and Topotarget provided funding for the study.

Author information

Author notes

    Authors and Affiliations

    1. Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA

      Hanna Bailey, Jordan P. McPherson, Erin B. Bailey, Theresa L. Werner, Sumati Gupta, Julia Batten, Sunil Sharma & Neeraj Agarwal

    2. Spectrum Pharmaceuticals, Irvine, CA, USA

      Guru Reddy & Gajanan Bhat

    Authors
    1. Hanna Bailey
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jordan P. McPherson
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Erin B. Bailey
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Theresa L. Werner
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Sumati Gupta
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Julia Batten
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Guru Reddy
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Gajanan Bhat
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Sunil Sharma
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Neeraj Agarwal
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Neeraj Agarwal.

    Ethics declarations

    Conflict of interest

    Guru Reddy and Gajanan Bhat are employees of Spectrum Pharmaceuticals. There are no other conflicts of interest reported by the remaining authors.

    Ethical approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

    Additional information

    Hanna Bailey and Jordan P. McPherson have contributed equally to this work.

    Guru Reddy: Conducted pharmacokinetics analysis.

    Appendix

    Appendix

    See Figs. 3, 4, 5, 6, and 7.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Bailey, H., McPherson, J.P., Bailey, E.B. et al. A phase I study to determine the pharmacokinetics and urinary excretion of belinostat and metabolites in patients with advanced solid tumors. Cancer Chemother Pharmacol 78, 1059–1071 (2016). https://doi.org/10.1007/s00280-016-3167-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00280-016-3167-7

    Keywords

    Search

    Navigation