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

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/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.

Figures

Figure 1

Pharmacodynamics of bortezomib(B) and PLD. (A) Inhibition of the chymotryptic activity of the 20S proteasome by B is shown as a function of the administered dose level (in mg/m2). The mean percentage inhibition 1 hour after each dose compared to the pretreatment baseline is shown for days 1 and 4. All data presented are from the first cycle of therapy. (B) The mean 20S proteasome inhibition one hour after each dose B alone on days 1 and 4 is compared to mean inhibition on days 8 and 11, when both B and PLD were present. (C) Specific activity of the chymotrypsin like proteasome protease is shown at baseline and one hour after bortezomib treatment on day 1 as a mean for each dose level. The units for specific activity are picomoles of fluorescent chromophore released per second per milligram of total protein. (D) Mean proteasome activity is shown at baseline and one hour after dosing with either bortezomib alone (days 1 and 4) or bortezomib in the presence of PLD (days 8 and 11).

Figure 1

Pharmacodynamics of bortezomib(B) and PLD. (A) Inhibition of the chymotryptic activity of the 20S proteasome by B is shown as a function of the administered dose level (in mg/m2). The mean percentage inhibition 1 hour after each dose compared to the pretreatment baseline is shown for days 1 and 4. All data presented are from the first cycle of therapy. (B) The mean 20S proteasome inhibition one hour after each dose B alone on days 1 and 4 is compared to mean inhibition on days 8 and 11, when both B and PLD were present. (C) Specific activity of the chymotrypsin like proteasome protease is shown at baseline and one hour after bortezomib treatment on day 1 as a mean for each dose level. The units for specific activity are picomoles of fluorescent chromophore released per second per milligram of total protein. (D) Mean proteasome activity is shown at baseline and one hour after dosing with either bortezomib alone (days 1 and 4) or bortezomib in the presence of PLD (days 8 and 11).

Figure 1

Pharmacodynamics of bortezomib(B) and PLD. (A) Inhibition of the chymotryptic activity of the 20S proteasome by B is shown as a function of the administered dose level (in mg/m2). The mean percentage inhibition 1 hour after each dose compared to the pretreatment baseline is shown for days 1 and 4. All data presented are from the first cycle of therapy. (B) The mean 20S proteasome inhibition one hour after each dose B alone on days 1 and 4 is compared to mean inhibition on days 8 and 11, when both B and PLD were present. (C) Specific activity of the chymotrypsin like proteasome protease is shown at baseline and one hour after bortezomib treatment on day 1 as a mean for each dose level. The units for specific activity are picomoles of fluorescent chromophore released per second per milligram of total protein. (D) Mean proteasome activity is shown at baseline and one hour after dosing with either bortezomib alone (days 1 and 4) or bortezomib in the presence of PLD (days 8 and 11).

Figure 1

Pharmacodynamics of bortezomib(B) and PLD. (A) Inhibition of the chymotryptic activity of the 20S proteasome by B is shown as a function of the administered dose level (in mg/m2). The mean percentage inhibition 1 hour after each dose compared to the pretreatment baseline is shown for days 1 and 4. All data presented are from the first cycle of therapy. (B) The mean 20S proteasome inhibition one hour after each dose B alone on days 1 and 4 is compared to mean inhibition on days 8 and 11, when both B and PLD were present. (C) Specific activity of the chymotrypsin like proteasome protease is shown at baseline and one hour after bortezomib treatment on day 1 as a mean for each dose level. The units for specific activity are picomoles of fluorescent chromophore released per second per milligram of total protein. (D) Mean proteasome activity is shown at baseline and one hour after dosing with either bortezomib alone (days 1 and 4) or bortezomib in the presence of PLD (days 8 and 11).

Figure 2

Figure 2a. A patient with cutaneous metastases had dramatic and rapid response shown here from cycle 1 to cycle 3 with time to progression over 4 months. Figure 2b. A patient with breast cancer hepatic metastases had partial response in her hepatic disease with time to progression 11 months.