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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Authors: | 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 |
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Affiliation: | E. Claire Dees, Bert H. O’Neil, Celeste M. Lindley, Frances Collichio, Lisa A. Carey, Jason Collins, William J. Riordan, Anastasia Ivanova, Dixie Esseltine and Robert Z. Orlowski |
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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. 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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Keywords: | Phase I Proteasome inhibition Bortezomib Pegylated liposomal doxorubicin Breast cancer |
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