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

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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.

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Acknowledgments

The authors would like to thank the nurses and research specialists of the University of Wisconsin Carbone Cancer Center Phase I Program and acknowledge the editorial assistance of Jane Saunders of FireKite during development of this publication. This study was supported in part by the University of Wisconsin Carbone Cancer Center UO1 CA062491 Early Clinical Trials of Anti-Cancer Agents Phase 1 grant and the Clinical and Translational Science Award 1UL1RR025011 from the National Center for Research Resources, NIH; Case Western Reserve University U01 CA62502; University of Pittsburgh Cancer Institute and Medical Center grants UO1-CA099168, UO1-CA69855, P30CA47904 and NIH/GCR #5M01 RR 00056; City of Hope National Medical Center General Clinical Research Center grant (M01 RRR00043); University of Texas Health Science Center grant UO1-CA 069853-14; USC/Norris Comprehensive Cancer Center grant UO1-CA 62505.

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Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, 600 Highland Ave, Madison, WI, 53792, USA

    Ticiana B. Leal & Daniel Mulkerin

  2. Comprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH, USA

    Scot C. Remick

  3. Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA

    Chris H. Takimoto & John Sarantopoulos

  4. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Ramesh K. Ramanathan & Merrill J. Egorin

  5. UC Davis Cancer Center, Sacramento, CA, USA

    Angela Davies

  6. Sydney Cancer Centre, Sydney, Australia

    Anne Hamilton

  7. Wayne State University, Detroit, MI, USA

    Patricia A. LoRusso

  8. City of Hope National Medical Center, Duarte, CA, USA

    Stephen Shibata

  9. USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    Heinz-Josef Lenz

  10. Beth Israel Deaconess Medical Center, Boston, MA, USA

    James Mier

  11. Montefiore Hospital, Albert Einstein College of Medicine, Bronx, NY, USA

    Sridhar Mani

  12. Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    John J. Wright & S. Percy Ivy

  13. Millennium Pharmaceuticals, Inc., Cambridge, MA, USA

    Rachel Neuwirth, Lisa von Moltke & Karthik Venkatakrishnan

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  1. Ticiana B. Leal
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  2. Scot C. Remick
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Corresponding author

Correspondence to Daniel Mulkerin.

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Leal, T.B., Remick, S.C., Takimoto, C.H. et al. Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. Cancer Chemother Pharmacol 68, 1439–1447 (2011). https://doi.org/10.1007/s00280-011-1637-5

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  • DOI: https://doi.org/10.1007/s00280-011-1637-5

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