Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 6, pp 1439–1447

Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study

  • Ticiana B. Leal
  • Scot C. Remick
  • Chris H. Takimoto
  • Ramesh K. Ramanathan
  • Angela Davies
  • Merrill J. Egorin
  • Anne Hamilton
  • Patricia A. LoRusso
  • Stephen Shibata
  • Heinz-Josef Lenz
  • James Mier
  • John Sarantopoulos
  • Sridhar Mani
  • John J. Wright
  • S. Percy Ivy
  • Rachel Neuwirth
  • Lisa von Moltke
  • Karthik Venkatakrishnan
  • Daniel Mulkerin
Original Article

Abstract

Purpose

To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.

Patients and Methods

Sixty-two adult cancer patients received intravenous bortezomib at 0.7–1.5 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m2 into five cohorts: normal renal function (≥60 ml/min/1.73 m2); mild dysfunction (40–59 ml/min/1.73 m2); moderate dysfunction (20–39 ml/min/1.73 m2); severe dysfunction (<20 ml/min/1.73 m2); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.

Results

Bortezomib escalation to the standard 1.3 mg/m2 dose was well tolerated in all patients with CrCl ≥20 ml/min/1.73 m2; 0.7 mg/m2 was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m2). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m2 in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.

Conclusion

Bortezomib 1.3 mg/m2 is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

Keywords

Renal function Bortezomib Toxicity Pharmacokinetics Pharmacodynamics 

Supplementary material

280_2011_1637_MOESM1_ESM.doc (340 kb)
Supplementary material 1 (DOC 340 kb)

References

  1. 1.
    Goldberg AL, Akopian TN, Kisselev AF et al (1997) New insights into the mechanisms and importance of the proteasome in intracellular protein degradation. Biol Chem 378:131–140PubMedGoogle Scholar
  2. 2.
    Zwickl P, Baumeister W, Steven A (2000) Dis-assembly lines: the proteosome and related ATPase-assisted proteases. Curr Opin Struct Biol 10:242–250PubMedCrossRefGoogle Scholar
  3. 3.
    Ciechanover A, Orian A, Schwartz AL (2000) Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22:442–451PubMedCrossRefGoogle Scholar
  4. 4.
    Hershko A (1997) Roles of ubiquitin -mediated proteolysis in cell cycle control. Curr Opin Struct Biol 9:788–799Google Scholar
  5. 5.
    Oikawa T, Sasaki T, Nakamura M et al (1998) The proteasome is involved in angiogenesis. Biochem Biophys Res Commun 246:243–248PubMedCrossRefGoogle Scholar
  6. 6.
    Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274:782–784PubMedCrossRefGoogle Scholar
  7. 7.
    Zetter BR (1993) Adhesion molecules in tumor metastasis. Semin Cancer Biol 4:215–218Google Scholar
  8. 8.
    Read MA, Neish AS, Luscinskas FW et al (1995) The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity 2:493–506PubMedCrossRefGoogle Scholar
  9. 9.
    Hideshima T, Richardson P, Chauhan D et al (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076PubMedGoogle Scholar
  10. 10.
    Hideshima T, Mitsiades C, Akiyama M et al (2003) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101:1530–1534PubMedCrossRefGoogle Scholar
  11. 11.
    Richardson PG, Sonneveld P, Schuster M et al (2007) Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110:3557–3560PubMedCrossRefGoogle Scholar
  12. 12.
    San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917PubMedCrossRefGoogle Scholar
  13. 13.
    Goy A, Bernstein SH, Kahl BS et al (2009) Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol 20:520–525PubMedCrossRefGoogle Scholar
  14. 14.
    San-Miguel JF, Richardson PG, Sonneveld P et al (2008) Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 22:842–849PubMedCrossRefGoogle Scholar
  15. 15.
    Dimopoulos MA, Richardson P, Schlag R et al (2008) A prospective, randomized, phase III study of bortezomib, melphalan, prednisone and thalidomide (VMPT) versus bortezomib, melphalan and prednisone (VMP) in elderly newly diagnosed myeloma patients. Blood 112:1727aGoogle Scholar
  16. 16.
    Therasse P, Arbuck SG, Eisenhauer EA et al (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 92:205–216PubMedCrossRefGoogle Scholar
  17. 17.
    Cheson BD, Bennett JM, Grever M et al (1996) National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87:4990–4997PubMedGoogle Scholar
  18. 18.
    Cheson BD, Horning SJ, Coiffier B et al (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244–1253PubMedGoogle Scholar
  19. 19.
    Blade J, Samson D, Reece D et al (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 102:1115–1123PubMedCrossRefGoogle Scholar
  20. 20.
    Prepared by a Committee of the Chronic Leukemia–Myeloma Task Force, National Cancer Institute (1968) Proposed guidelines for protocol studies. II. Plasma cell myeloma. Cancer Chemother Rep 3 1:17–39 Google Scholar
  21. 21.
    Lightcap ES, McCormack TA, Pien CS et al (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46:673–683PubMedGoogle Scholar
  22. 22.
    Stewart AK, Sullivan D, Lonial S et al (2006) Pharmacokinetic (PK) and pharmacodynamics (PD) study of two doses of bortezomib (Btz) in patients with relapsed multiple myeloma (MM). Blood 108:1008aGoogle Scholar
  23. 23.
    Melamed J (2005) Repeat-dose pharmacokinetics and pharmacodynamics of bortezomib in patients with relapsed multiple myeloma. Report No. M34103-058 CSR. Millennium Pharmaceuticals, Inc., CambridgeGoogle Scholar
  24. 24.
    Chanan-Khan AA, Richardson P, Lonial S et al (2005) Safety and efficacy of bortezomib in multiple myeloma patients with renal failure requiring dialysis. Blood 106:716aCrossRefGoogle Scholar
  25. 25.
    Ludwig H, Adam Z, Hajek R et al (2008) Bortezomib-doxorubicin-dexamethasone (BDD) for reversal of acute light chain induced renal failure (ARF) in multiple myeloma (MM). Results from a phase II study. Blood 112:Abstr 3682Google Scholar
  26. 26.
    Pekol T, Daniels JS, Labutti J et al (2005) Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos 33:771–777PubMedCrossRefGoogle Scholar
  27. 27.
    Leger F, Seronie-Vivien S, Makdessi J et al (2002) Impact of the biochemical assay for serum creatinine measurement on the individual carboplatin dosing: a prospective study. Eur J Cancer 38:52–56PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ticiana B. Leal
    • 1
  • Scot C. Remick
    • 2
  • Chris H. Takimoto
    • 3
  • Ramesh K. Ramanathan
    • 4
  • Angela Davies
    • 5
  • Merrill J. Egorin
    • 4
  • Anne Hamilton
    • 6
  • Patricia A. LoRusso
    • 7
  • Stephen Shibata
    • 8
  • Heinz-Josef Lenz
    • 9
  • James Mier
    • 10
  • John Sarantopoulos
    • 3
  • Sridhar Mani
    • 11
  • John J. Wright
    • 12
  • S. Percy Ivy
    • 12
  • Rachel Neuwirth
    • 13
  • Lisa von Moltke
    • 13
  • Karthik Venkatakrishnan
    • 13
  • Daniel Mulkerin
    • 1
  1. 1.University of Wisconsin Carbone Cancer CenterMadisonUSA
  2. 2.Comprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve UniversityClevelandUSA
  3. 3.Institute for Drug Development, Cancer Therapy and Research CenterUniversity of Texas Health Science CenterSan AntonioUSA
  4. 4.University of Pittsburgh Cancer InstitutePittsburghUSA
  5. 5.UC Davis Cancer CenterSacramentoUSA
  6. 6.Sydney Cancer CentreSydneyAustralia
  7. 7.Wayne State UniversityDetroitUSA
  8. 8.City of Hope National Medical CenterDuarteUSA
  9. 9.USC/Norris Comprehensive Cancer CenterLos AngelesUSA
  10. 10.Beth Israel Deaconess Medical CenterBostonUSA
  11. 11.Montefiore HospitalAlbert Einstein College of MedicineBronxUSA
  12. 12.Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaUSA
  13. 13.Millennium Pharmaceuticals, Inc.CambridgeUSA

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