[PI & pharmacologic data for Velcade]
>>Clin Cancer Res. 2005 May 1;11(9):3410-6.
A Phase I and Pharmacologic Trial of Two Schedules of the Proteasome Inhibitor, PS-341 (Bortezomib, Velcade), in Patients with Advanced Cancer.
Dy GK, Thomas JP, Wilding G, Bruzek L, Mandrekar S, Erlichman C, Alberti D, Binger K, Pitot HC, Alberts SR, Hanson LJ, Marnocha R, Tutsch K, Kaufmann SH, Adjei AA.
Authors' Affiliations: Mayo Clinic, Rochester, Minnesota, and University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin.
PURPOSE: 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 4 female) received PS-341 twice weekly 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 thrombocytopenia, which was dose limiting at 1.7 mg/m(2) (schedule I) and 1.6 mg/m(2) (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. 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/m(2) for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m(2), 52% at 0.9 mg/m(2), and 75% at 1.25 mg/m(2). 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/m(2) twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.<<
Apologies if this data has already been posted. Wonder how the patients with solid tumors did, assuming there were any.
Cheers, Tuck |
