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A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors

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Abstract

Purpose

Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.

Methods

Patients received bortezomib, 0.9–1.5 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m2, on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination.

Results

A total of 37 patients with four median prior therapies were treated. Frequent grade 1–2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib at 1.2 mg/m2, and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m2. Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m2 levels, bortezomib at 1.3 mg/m2 and PLD at 30 mg/m2 are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs.

Conclusions

A regimen of bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11 with PLD, 30 mg/m2, on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.

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Acknowledgments

The authors would like to thank Beth Humes for research nursing, Susan Natoli for regulatory assistance, Anandhi Johri, Mary Jo Lehman, Henry Bell, and Paul Jones for help with data collection and management, and most importantly the patients who participated in this study and their families for their courage and contribution to the evaluation of new cancer therapies.

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    E. Claire Dees, Bert H. O’Neil, Frances Collichio, Lisa A. Carey, Anastasia Ivanova & Robert Z. Orlowski

  2. Division of Hematology and Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, CB 7305/ 3009 Old Clinic Building, Chapel Hill, NC, 27599, USA

    E. Claire Dees, Bert H. O’Neil, Frances Collichio, Lisa A. Carey & Robert Z. Orlowski

  3. School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Celeste M. Lindley & Jason Collins

  4. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Robert Z. Orlowski

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

    William J. Riordan & Dixie Esseltine

Authors
  1. E. Claire Dees
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  2. Bert H. O’Neil
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  4. Frances Collichio
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  10. Robert Z. Orlowski
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Corresponding author

Correspondence to E. Claire Dees.

Additional information

Supported in part by grants from the following: Millennium Pharmaceuticals, Inc., General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health(RR00046), National Cancer Institute SPORE in Breast Cancer (5-P50-CA58223-09A1 H.S. Earp), National Inst. of Health (K23-RR16536 ECD), Leukemia and Lymphoma Society (6096-07 RZO), and National Cancer Institute (RO1 CA102278 RZO).

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Dees, E.C., O’Neil, B.H., Lindley, C.M. et al. A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors. Cancer Chemother Pharmacol 63, 99–107 (2008). https://doi.org/10.1007/s00280-008-0716-8

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  • DOI: https://doi.org/10.1007/s00280-008-0716-8

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