A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors.
OBJECTIVE
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/m(2), on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m(2), 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/m(2), and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m(2). 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/m(2) levels, bortezomib at 1.3 mg/m(2) and PLD at 30 mg/m(2) 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/m(2) on days 1, 4, 8, and 11 with PLD, 30 mg/m(2), on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.
Dees
E Claire
EC
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. claire_dees@med.unc.edu
O'Neil
Bert H
BH
Lindley
Celeste M
CM
Collichio
Frances
F
Carey
Lisa A
LA
Collins
Jason
J
Riordan
William J
WJ
Ivanova
Anastasia
A
Esseltine
Dixie
D
Orlowski
Robert Z
RZ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016879:Salvage Therapy; D016896:Treatment Outcome
D001897:Boronic Acids; D008081:Liposomes; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000069286:Bortezomib; D004317:Doxorubicin