TY - JOUR
T1 - A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (Bortezomib, Velcade), in patients with advanced cancer
AU - Dy, Grace K.
AU - Thomas, James P.
AU - Wilding, George
AU - Bruzek, Laura
AU - Mandrekar, Sumithra
AU - Erlichman, Charles
AU - Alberti, Dona
AU - Binger, Kim
AU - Pitot, Henry C.
AU - Alberts, Steven R.
AU - Hanson, Lorelei J.
AU - Marnocha, Rebecca
AU - Tutsch, Kendra
AU - Kaufmann, Scott H.
AU - Adjei, Alex A.
PY - 2005/5/1
Y1 - 2005/5/1
N2 - To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. Patients and Methods: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and female) received PS-341 twice vveekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. Results: The most common toxicity was thiobocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule 1. Grade ≥ 3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade ≥ 3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2 and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. Conclusion: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.
AB - To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. Patients and Methods: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and female) received PS-341 twice vveekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. Results: The most common toxicity was thiobocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule 1. Grade ≥ 3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade ≥ 3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2 and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. Conclusion: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.
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U2 - 10.1158/1078-0432.CCR-04-2068
DO - 10.1158/1078-0432.CCR-04-2068
M3 - Article
C2 - 15867242
AN - SCOPUS:20944450476
SN - 1078-0432
VL - 11
SP - 3410
EP - 3416
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -