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Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies

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Abstract

Background

Preclinical data suggest synergistic activity of bortezomib, gemcitabine, and liposomal doxorubicin. Because tolerance to therapy may be attenuated in elderly patients, we performed an age-stratified phase I trial of this combination.

Patients and methods

Two parallel age-stratified arms (<65 and ≥65 years old) were accrued (3 + 3 design). Starting doses included bortezomib 0.7 mg/m2 (days 1 and 8), gemcitabine 500 mg/m2 (days 1 and 8), and liposomal doxorubicin 20 mg/m2 (day 1).

Results

In the <65-year-old group, 65 patients were treated; the maximum-tolerated dose was bortezomib 1.3 mg/m2, gemcitabine 800 mg/m2, and liposomal doxorubicin 35 mg/m2. In the ≥65-year-old group, 28 patients were treated; the recommended phase II dose was bortezomib 1.0 mg/m2, gemcitabine 800 mg/m2, and liposomal doxorubicin 20 mg/m2. Dose-limiting toxicities included thrombocytopenia and neutropenia. The most common toxicities were mild cytopenias, fatigue, and neuropathy. Ten patients achieved partial responses (6 of 7 patients with cutaneous T-cell lymphoma; 4 of 16 patients with small cell carcinomas, including lung, prostate, ovarian, and nasopharyngeal).

Conclusion

Combination of bortezomib, gemcitabine, and liposomal doxorubicin is well tolerated, but with a lower recommended phase II dose in elderly patients, and demonstrated antitumor activity, especially in T-cell and small cell histology malignancies.

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Acknowledgments

We would like to thank Christine Eberle for assistance with manuscript preparation and Joann Aaron for editorial assistance. No funding was received for this work.

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Authors and Affiliations

  1. Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program)-Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    G. S. Falchook, D. S. Hong, J. Wheler, A. Naing, J. Lim & R. Kurzrock

  2. Division of Internal Medicine, Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    M. Duvic

Authors
  1. G. S. Falchook
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  2. M. Duvic
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  3. D. S. Hong
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  4. J. Wheler
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  5. A. Naing
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  6. J. Lim
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  7. R. Kurzrock
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Correspondence to G. S. Falchook.

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Falchook, G.S., Duvic, M., Hong, D.S. et al. Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies. Cancer Chemother Pharmacol 69, 1117–1126 (2012). https://doi.org/10.1007/s00280-011-1808-4

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  • DOI: https://doi.org/10.1007/s00280-011-1808-4

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