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01.12.2008 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2008

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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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Titel: A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors
verfasst von: 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
Publikationsdatum: 01.12.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2008
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0716-8

Springer Medizin

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