Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We therefore conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.
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.
A total of 37 patients with 4 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 1/6 patients receiving bortezomib at 1.2 mg/m2, and grade 3 nausea, vomiting, and diarrhea in 1/6 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.
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.