Skip to main content

Advertisement

SpringerLink
Log in

A dose-finding and pharmacodynamic study of bortezomib in combination with weekly paclitaxel in patients with advanced solid tumors

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

Abstract

Purpose

A phase I study to determine the maximum tolerated dose (MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors.

Patients and methods

Eligible patients received escalating doses of intravenous (IV) bortezomib (0.6–2 mg/m2) on days 2 and 9 and IV paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. Dose escalation was based on two end-points: not exceeding 80% 20S-proteasome inhibition (20-S PI) and the development of dose-limiting toxicity defined as grade 3 or greater non-hematologic or grade 4 hematologic toxicities.

Results

Forty-five patients with advanced solid tumors and a median of 3 prior chemotherapy regimens (range 0–9), received 318 doses (median 5, range 1–34) of bortezomib and paclitaxel. Dose-related inhibition of 20-S PI was observed with a maximum inhibition of 70–80% at the MTD of 1.8 mg/m2 of bortezomib. At the MTD (N = 9) the following toxicities were observed: grade 4 neutropenia without fever (n = 2) and cerebrovascular ischemia (n = 1); grade 3 neutropenia (n = 3), diarrhea (n = 2), nausea (n = 1), and fatigue (n = 1); grade 2 fatigue (n = 5), diarrhea (n = 4), and dyspnea (n = 2). There was one partial response in a patient with an eccrine porocarcinoma. Stabilization of disease was observed in 7 (16%) patients, 3 of whom had advanced pancreatic cancer.

Conclusion

Sequential paclitaxel and bortezomib in previously treated patients with advanced solid tumors resulted in acceptable toxicity and no evidence of interaction. The recommended phase II dose of bortezomib in combination with weekly paclitaxel was 1.8 mg/m2.

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

Similar content being viewed by others

References

  1. Adams J (2003) The proteasome: structure, function, and role in the cell. Cancer Treat Rev 29(Suppl 1):3–9

    Article  CAS  PubMed  Google Scholar 

  2. Ciechanover A, Schwartz AL (1998) The ubiquitin–proteasome pathway: the complexity and myriad functions of proteins death [comment]. Proc Natl Acad Sci USA 95:2727–2730

    Article  CAS  PubMed  Google Scholar 

  3. Adams J (2002) Development of the proteasome inhibitor PS-341. Oncologist 7:9–16

    Article  CAS  PubMed  Google Scholar 

  4. Cusack JC (2003) Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. Cancer Treat Rev 29(Suppl 1):21–31

    Article  CAS  PubMed  Google Scholar 

  5. Nencioni A, Grunebach F, Patrone F et al (2007) Proteasome inhibitors: antitumor effects and beyond. Leukemia 21:30–36

    Article  CAS  PubMed  Google Scholar 

  6. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin–proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78:773–785

    Article  CAS  PubMed  Google Scholar 

  7. Ling YH, Liebes L, Ng B et al (2002) PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 1:841–849

    CAS  PubMed  Google Scholar 

  8. Richardson PG, Sonneveld P, Schuster MW (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma [see comment]. N Engl J Med 352:2487–2498

    Article  CAS  PubMed  Google Scholar 

  9. Jagannath S, Barlogie B, Berenson J et al (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165–172

    Article  CAS  PubMed  Google Scholar 

  10. Richardson PG, Barlogie B, Berenson J (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma [see comment]. N Engl J Med 348:2609–2617

    Article  CAS  PubMed  Google Scholar 

  11. Millennium Pharmaceuticals I. Velcade Full Prescribing Information. June 2008

  12. Papandreou CN, Daliani DD, Nix D et al (2004) Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108–2121

    Article  CAS  PubMed  Google Scholar 

  13. Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14:1649–1657

    Article  CAS  PubMed  Google Scholar 

  14. Milano A, Iaffaioli RV, Caponigro F (2007) The proteasome: a worthwhile target for the treatment of solid tumours? Eur J Cancer 43:1125–1133

    Article  CAS  PubMed  Google Scholar 

  15. Mitsiades CS, McMillin D, Kotoula V et al (2006) Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro. J Clin Endocrinol Metab 91:4013–4021

    Article  CAS  PubMed  Google Scholar 

  16. Orlowski RZ, Eswara JR, Lafond-Walker A et al (1998) Tumor growth inhibition induced in a murine model of human Burkitt’s lymphoma by a proteasome inhibitor. Cancer Res 58:4342–4348

    CAS  PubMed  Google Scholar 

  17. Teicher BA, Ara G, Herbst R et al (1999) The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5:2638–2645

    CAS  PubMed  Google Scholar 

  18. Orlowski RZ (1999) The role of the ubiquitin–proteasome pathway in apoptosis. Cell Death Differ 6:303–313

    Article  CAS  PubMed  Google Scholar 

  19. Cresta SSC, Catapano CV, Gallerani E, Passalacqua D, Rinaldi A, Bertoni F, Vigano L, maur M, Capri G, Maccioni E, Tosi D, Gianni L (2008) Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumors. Eur J Cancer. doi:10.1016/j.ejca.2008.05.022

  20. Ma C, Mandrekar SJ, Alberts SR et al (2007) A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies. Cancer Chemother Pharmacol 59:207–215

    Article  CAS  PubMed  Google Scholar 

  21. Canfield SE, Zhu K, Williams SA, McConkey DJ (2006) Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells. Mol Cancer Ther 5:2043–2050

    Article  CAS  PubMed  Google Scholar 

  22. Adams J (2002) Proteasome inhibitors as new anticancer drugs. Curr Opin Oncol 14:628–634

    Article  CAS  PubMed  Google Scholar 

  23. Gehan EA, Tefft MC (2000) Will there be resistance to the RECIST (Response Evaluation Criteria in Solid Tumors)? [comment]. J Natl Cancer Inst 92:179–181

    Article  CAS  PubMed  Google Scholar 

  24. Lightcap ES, McCormack TA, Pien CS et al (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46:673–683

    CAS  PubMed  Google Scholar 

  25. Aron JL, Parthun MR, Marcucci G et al (2003) Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. Blood 102:652–658

    Article  CAS  PubMed  Google Scholar 

  26. Yang CH, Gonzalez-Angulo AM, Reuben JM et al (2006) Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol 17:813–817

    Article  CAS  PubMed  Google Scholar 

  27. Aghajanian C, Soignet S, Dizon DS et al (2002) A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505–2511

    CAS  PubMed  Google Scholar 

  28. Awada A, Albanell J, Canney PA et al (2008) Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study. Br J Cancer 98:1500–1507

    Article  CAS  PubMed  Google Scholar 

  29. Cohen SJ, Engstrom PF, Lewis NL et al (2008) Phase I study of capecitabine and oxaliplatin in combination with the proteasome inhibitor bortezomib in patients with advanced solid tumors. Am J Clin Oncol 31:1–5

    Article  CAS  PubMed  Google Scholar 

  30. Dreicer R, Petrylak D, Agus D et al (2007) Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer. Clin Cancer Res 13:1208–1215

    Article  CAS  PubMed  Google Scholar 

  31. Pinkus H, Mehregan AH (1963) Epidermotropic eccrine carcinoma: a case combining features of eccrine poroma and Paget’s dermatosis. Arch Dermatol 88:597–606

    CAS  PubMed  Google Scholar 

  32. Snow SN, Reizner GT (1992) Mucinous eccrine carcinoma of the eyelid. Cancer 70:2099–2104

    Article  CAS  PubMed  Google Scholar 

  33. Robson A, Greene J, Ansari N (2001) Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases [see comment]. Am J Surg Pathol 25:710–720

    Article  CAS  PubMed  Google Scholar 

  34. Gutermuth J, Audring H, Voit C et al (2004) Antitumour activity of paclitaxel and interferon-alpha in a case of metastatic eccrine porocarcinoma. J Eur Acad Dermatol Venereol 18:477–479

    Article  CAS  PubMed  Google Scholar 

  35. Holcomb B, Yip-Schneider M, Schmidt CM (2008) The role of nuclear factor kappaB in pancreatic cancer and the clinical applications of targeted therapy. Pancreas 36:225–235

    Article  CAS  PubMed  Google Scholar 

  36. Ashamalla H, Zaki B, Mokhtar B et al. (2003) Hyperfractionated radiotherapy and paclitaxel for locally advanced/unresectable pancreatic cancer [erratum appears in Int J Radiat Oncol Biol Phys. Mar 15; 55(4):1158]. Int J Radiat Oncol Biol Phys 55: 679–687

    Google Scholar 

Download references

Acknowledgments

The project described was supported by Grant Number U01-CA76576 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer institute or the National Institutes of Health. The authors wish to thank the patients who participated in this trial; the many nurses, nurse practitioners, and patient care associates who assisted in the care of these patients in the Clinical Treatment Unit, JamesCare Dublin Clinic, and the Immediate Care Center; and acknowledge the contributions of Bill Riordan, Lisa O’Brien, and Jeannie Pierce at Millennium Pharmaceuticals in performing the 20S proteasome assay. The project described was supported by Grant Number U01-CA76576 from the National Cancer Institute.

Author information

Authors and Affiliations

  1. The Ohio State University, B401, Starling Loving Hall, 320 W 10th av, Columbus, OH, 43210, USA

    Bhuvaneswari Ramaswamy, Tanios Bekaii-Saab, Larry J. Schaaf, Gregory B. Lesinski, David M. Lucas, Donn C. Young, Amy S. Ruppert, John C. Byrd, Kristy Culler, Diedre Wilkins, John J. Wright, Michael R. Grever & Charles L. Shapiro

Authors
  1. Bhuvaneswari Ramaswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tanios Bekaii-Saab
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Larry J. Schaaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregory B. Lesinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David M. Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donn C. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Amy S. Ruppert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John C. Byrd
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kristy Culler
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Diedre Wilkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John J. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael R. Grever
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Charles L. Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bhuvaneswari Ramaswamy.

Additional information

Abstract was published in 2005 ASCO Annual meeting.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ramaswamy, B., Bekaii-Saab, T., Schaaf, L.J. et al. A dose-finding and pharmacodynamic study of bortezomib in combination with weekly paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 66, 151–158 (2010). https://doi.org/10.1007/s00280-009-1145-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-009-1145-z

Keywords

Search

Navigation