Cancer Chemotherapy and Pharmacology

, Volume 63, Issue 1, pp 99–107

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

  • E. Claire Dees
  • Bert H. O’Neil
  • Celeste M. Lindley
  • Frances Collichio
  • Lisa A. Carey
  • Jason Collins
  • William J. Riordan
  • Anastasia Ivanova
  • Dixie Esseltine
  • Robert Z. Orlowski
Original Article

DOI: 10.1007/s00280-008-0716-8

Cite this article as:
Dees, E.C., O’Neil, B.H., Lindley, C.M. et al. Cancer Chemother Pharmacol (2008) 63: 99. doi:10.1007/s00280-008-0716-8

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.

Keywords

Phase I Proteasome inhibition Bortezomib Pegylated liposomal doxorubicin Breast cancer 

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • E. Claire Dees
    • 1
    • 2
  • Bert H. O’Neil
    • 1
    • 2
  • Celeste M. Lindley
    • 3
  • Frances Collichio
    • 1
    • 2
  • Lisa A. Carey
    • 1
    • 2
  • Jason Collins
    • 3
  • William J. Riordan
    • 5
  • Anastasia Ivanova
    • 1
  • Dixie Esseltine
    • 5
  • Robert Z. Orlowski
    • 1
    • 2
    • 4
  1. 1.Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Division of Hematology and Oncology, Department of Medicine, School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Department of PharmacologyUniversity of North Carolina at Chapel HillChapel HillUSA
  5. 5.Millennium Pharmaceuticals, IncCambridgeUSA

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