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A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer

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Abstract

Purpose

This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies.

Patients and methods

Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m2 of bortezomib with 15 mg/m2 of doxorubicin to 1.5 mg/m2 of bortezomib with 20 mg/m2 of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates.

Results

The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m2 bortezomib, 20 mg/m2 doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m2 bortezomib, 15 mg/m2 doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients.

Conclusions

Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m2 intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease.

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Acknowledgments

The authors are grateful to Dr. Arthur Haas (Louisiana State University) and Mr. Richard Bohnsack (Medical College of Wisconsin) for providing the anti-ubiquitin conjugate antibody.

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Authors and Affiliations

  1. University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, K4/548 CSC, 600 Highland Avenue, Madison, WI, 53792, USA

    Noelle K. LoConte, Dona Alberti, Jennifer Heideman, Kimberly Binger, Rebecca Marnocha, Peter Geiger, Jens Eickhoff, George Wilding & Jill Kolesar

  2. The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA

    James P. Thomas

  3. University of Wisconsin School of Pharmacy, Madison, WI, 53792, USA

    Kyle Utecht & Jill Kolesar

Authors
  1. Noelle K. LoConte
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  2. James P. Thomas
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  3. Dona Alberti
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  4. Jennifer Heideman
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  5. Kimberly Binger
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  6. Rebecca Marnocha
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  7. Kyle Utecht
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  8. Peter Geiger
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  9. Jens Eickhoff
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  10. George Wilding
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  11. Jill Kolesar
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Corresponding author

Correspondence to Noelle K. LoConte.

Additional information

Supported by grant: U01 CA062491 “Early Clinical Trials of Anti-Cancer Agents With Phase I Emphasis, NCI” and M01 RR03186 “General Clinical Research Center Program of The National Center for Research Resources, NIH”.

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LoConte, N.K., Thomas, J.P., Alberti, D. et al. A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer. Cancer Chemother Pharmacol 63, 109–115 (2008). https://doi.org/10.1007/s00280-008-0719-5

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  • DOI: https://doi.org/10.1007/s00280-008-0719-5

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