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

To: Ian@SI who wrote (2317)	2/20/2005 12:42:47 PM
From: Ian@SI	Read Replies (1) \| Respond to of 3044

Part 2: MLN2704 in patients with advanced androgen independent metastatic prostate cancer; updated results A single ascending dose phase I study of MLN2704, led by Howard I. Scher, M.D. at Memorial Sloan-Kettering, New York and Mario Eisenberger, M.D. at Johns Hopkins Oncology Center, Maryland enrolled 23 patients and examined the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics and immunogenicity of MLN2704. Patients received MLN2704 at doses ranging from 18 to 343mg/m2. Responses in patients with measurable disease were evaluated based on the RECIST (Response Evaluation Criteria In Solid Tumors) criteria and confirmed four to six weeks after the first documentation of a complete or partial response. In addition, anti-tumor activity was evaluated based on a sustained PSA decline of at least 50 percent confirmed by two separate measurements at least four weeks apart. Dose escalation continued if no dose- limiting toxicity was observed. Investigators reported the following results: * Of 11 patients with measurable disease, one patient treated with a 264mg/m2 dose, achieved a durable partial response, including a PSA decline of more than 50 percent . This patient received 14 doses prior to measurable disease progression at 47 weeks; * One additional patient, treated with a 343mg/m2 dose, achieved a PSA decline of more than 50 percent that persisted for 24 weeks; * Four patients achieved stable disease; * Toxicities greater than grade three occurred in three patients including an episode of uncomplicated febrile neutropenia with lymphopenia and leukopenia, lymphopenia, and a transient grade three elevation in hepatic transaminases. No grade four toxicities were observed; and * No immunogenicity was observed despite repeat dosing.

To: Ian@SI who wrote (2317)	2/17/2006 2:34:18 PM
From: tuck	Respond to of 3044

[Phase I Trial of Bortezomib in Combination with Docetaxel in Patients with Advanced Solid Tumors] >>Clinical Cancer Research Vol. 12, 1270-1275, February 2006 Phase I Trial of Bortezomib in Combination with Docetaxel in Patients with Advanced Solid Tumors Wells A. Messersmith1, Sharyn D. Baker1, Lance Lassiter1, Rana A. Sullivan1, Kimberly Dinh1, Virna I. Almuete1, John J. Wright2, Ross C. Donehower1, Michael A. Carducci1 and Deborah K. Armstrong1 Authors' Affiliations: 1 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland and 2 Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, Maryland Requests for reprints: Wells Messersmith, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, CRB 1M88, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-502-6873; Fax: 410-614-9006; E-mail: wmesser1@jhmi.edu. Purpose: Bortezomib (PS-341), a first-in-class proteasome inhibitor, is metabolized by deboronation involving cytochrome P4503A (CYP3A), which also metabolizes docetaxel. Preclinical studies have shown synergy between bortezomib and taxanes. We conducted a phase I study combining bortezomib and docetaxel in refractory solid tumor patients. Experimental Design: Patients received escalating doses of weekly docetaxel (days 1 and 8) and twice weekly bortezomib (days 2, 5, 9, and 12) in 3-week cycles. Two subjects were enrolled at each dose level, with cohort expansion to six for dose-limiting toxicity (DLT). Dose levels 1, 2, and 3 consisted of docetaxel/bortezomib 25/0.8, 25/1.0, and 30/1.0 mg/m2, respectively. CYP3A activity and docetaxel pharmacokinetic studies were conducted, and proteasome inhibition was assessed. Results: Fourteen patients received a total of 34 cycles of treatment. Dose level 2 was expanded for DLT that occurred in two of six patients consisting of febrile neutropenia in one patient and grade 3 thrombocytopenia in one patient. One patient received two cycles at dose level 3 with dose reduction to dose level 2, where grade 3 thrombocytopenia occurred at cycle 3. Both episodes of grade 3 thrombocytopenia were transient (<7 days). Dose level 1 was then expanded to six patients where no DLTs occurred. CYP3A activity and docetaxel clearance did not change between weeks 1 and 5. Conclusions: The maximum tolerated dose was docetaxel 25 mg/m2 (days 1 and 8) with bortezomib 0.8 mg/m2 (days 2, 5, 9, and 12) given every 21 days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance. << Cheers, Tuck