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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (1420)	3/14/2003 7:00:07 PM
From: Miljenko Zuanic	Respond to of 3044

Tuck, Several factors indicate synergy in activity between 341 and cytotoxic/cytostatic agents. By summer we may know bit more. Miljenko

To: tuck who wrote (1420)	3/15/2003 12:11:15 AM
From: microcapfun	Read Replies (1) \| Respond to of 3044

>>AACR presentations include some solid tumor data on PS341. Seems as though it will work well with anti cancer agents that induce hypoxia in solid tumors. Use bortezomib as your search term for the relevant abstract.<< This is the only Velcade AACR abstract I found with clinical data, and it doesn't say anything about efficacy. >>Abstract Number: 5347 Pharmacokinetics of gemcitabine and the proteasome inhibitor bortezomib (formerly PS-341) in adult patients with solid malignancies Darrell Nix, David P. Ryan, Joseph Paul Eder, Panos Fidias, Roberto Guerciolini, Narith Sao, Jeffrey Supko, Millennium Pharmaceuticals, Cambridge, MA; Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA. bortezomib (VELCADETM ) is a potent and selective inhibitor of the proteasome with significant antiproliferative activity against in vitro and in vivo tumor models. Its combination with chemotherapeutic agents such as irinotecan, docetaxel, cisplatin, gemcitabine, and dexamethasone results in enhanced antitumor activity in such models. A phase I clinical trial was undertaken to evaluate the administration of bortezomib in combination with gemcitabine. bortezomib was given by rapid i.v. injection on days 1 and 4, with the dose on day 1 immediately followed by a 30 min i.v. infusion of gemcitabine, for two consecutive weeks every 21 days. Starting doses were 1.0 mg/m2 bortezomib and 500 mg/m2 gemcitabine. Initially, the gemcitabine dose was sequentially escalated to 800 and 1000 mg/m2, after which bortezomib dose increased to 1.3 mg/m2, to determine the maximum tolerated dose (MTD) of the combination. Groups of at least three patients were evaluated at each dose level. Sampling to define the plasma pharmacokinetics of bortezomib was performed for the initial dose on both weeks, while gemcitabine pharmacokinetics were determined at the second weekly dose. Pharmacokinetic parameters were estimated by noncompartmental methods. The MTD of the combination was 1.0 mg/m2 bortezomib and 1000 mg/m2 gemcitabine. Analysis of pharmacokinetic data for a group of 11 patients treated with 1.0 mg/m2 bortezomib revealed that plasma levels decayed in a bi-exponential manner. Although the peak plasma concentration on day 1 (176 ± 154 ng/mL) and day 8 (139 ± 115 ng/mL) were similar, there was a marked decrease in the total body clearance from 55.1 ± 27.3 L/h on day 1 to 24.1 ± 7.7 L/h on day 8. This change in drug disposition was associated with a 3-fold prolongation of the apparent terminal phase half-life, from 6.0 ± 5.3 h on day 1 to 19.9 ± 12.6 h on day 8, whereas the apparent volume of distribution showed only a modest difference between days 1 (396 ± 217 L) and 8 (638 ± 360 L). Pharmacokinetic parameters of gemcitabine were comparable to historical data. Mean values (±SD) for a group of 7 patients receiving 1000 mg/m2 gemcitabine were as follows: peak plasma concentration, 47.3 ± 15.9 ìM; biological half-life, 13.4 ± 4.4 min; total body clearance, 121 ± 43 L/h/m2; apparent volume of distribution, 32 ± 18 L/m2. The results of these studies indicate that there are substantial changes in the disposition of bortezomib upon repeated dosing at intervals of 3 to 4 days. Similar changes were observed when the same dosing schedule of bortezomib alone was evaluated in cynomolgus monkeys. The plasma pharmacokinetics of gemcitabine does not appear to be affected when given together with bortezomib. Presenter: Darrell Nix Affiliation: Millennium Pharmaceuticals, Cambridge, MA . Email: amclaugh@mpi.com <<