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

To: Icebrg who wrote (1941)	11/20/2003 6:39:26 PM
From: Miljenko Zuanic	Respond to of 3044

Now PFE (was Pharm.) FLT3 inhibitor. Significant toxicity at higher doses (100 mg/day). Re-growth after breaks!???? B16 Phase II study of SU11248 in patients with advanced malignancies incorporating PET imaging. Guy C. Toner, Paul L. Mitchell, Richard De Boer, Peter Gibbs, Rod Hicks, Andrew M. Scott, Grant McArthur, Nicoletta Brega, Giorgio Massimini, and Timothy McCarthy. Centre for Developmental Cancer Therapeutics, Melbourne, Australia, Pfizer, Nerviano, Italy, and Pfizer, St Louis, MO. SU11248 is an orally available multi-targeted tyrosine kinase inhibitor with selectivity for PDGF receptors, VEGF receptors, KIT and FLT3. We conducted an open, multicenter, exploratory study of SU11248 using 4 PET scanning modalities to evaluate metabolic changes in tumors and to compare PET changes with conventional response and biomarker analyses. SU11248 was administered at a starting dose of 50 mg/day, in 6-week cycles comprising 4 weeks of daily oral dosing followed by a 2-week rest. Eligible patients had KPS >60 and advanced malignancies which were refractory to standard therapies. The principal endpoint was 20% reduction in fluorodeoxy glucose (FDG) standard uptake value (SUV) on serial PET scans. Preliminary results are available for the first 41 patients. Patients: 24 males, 17 females; median age 57 (range 18-79); median KPS 90 (range 70-100); median no. of prior treatments 2 (range 0-8). Cancer type: colorectal 7, sarcoma 7, melanoma 6, renal 5, others 16. Median time on study: 57 days (range 8-457). Safety: Common toxicities included lethargy, thrombocytopenia, neutropenia, odynophagia, pigmentation of skin and depigmentation of hair. 27 patients (66%) completed the planned 12 week study period. 27 patients (66%) had grade 3 or 4 toxicities. 2 patients died with infection that was possibly treatment-related. Efficacy: PET responses at 4 weeks were: 17 (41%) had ¡Ý20% reduction in FDG SUV, 8 (19%) were stable, 6 (15%) had mixed response, 6 (15%) progressed and 4 (10%) were not evaluable. RECIST responses after 12 weeks were 2 PR (5%) and 12 SD (29%). Clinical benefit (PR+SD) ocurred in 34%. Rapid shrinkage of some tumor masses was observed. Central necrosis of tumors with a viable rim of persistent malignancy was observed more frequently. Evidence for target modulation includes elevation of plasma VEGF and falls in soluble VEGF-R2 levels during therapy. IHC studies in patients with biopsy samples show changes in VEGF-R2, ki-67, and other markers in selected cases. Rapid re-growth of tumor masses during breaks in treatment was observed in some cases. Pharmacokinetics: Target trough blood levels (>100 ng/ml) at day 28 were achieved in 13 of 34 cases (38%) with a further 11 (32%) reaching potentially therapeutic (50-100ng/ml) levels. Higher levels correlated with PET response (p=0.003) and clinical benefit (p=0.007). Conclusions: SU11248 has biologic effects on advanced malignancies. PET response and central tumor necrosis have been observed frequently. Conventional responses have also been observed. Accrual to an additional cohort is ongoing in an attempt to assess the frequency and significance of re-growth during breaks from treatment. Further exploration of the correlation between efficacy, toxicity and drug exposure is needed.

To: Icebrg who wrote (1941)	12/16/2003 9:35:39 AM
From: Icebrg	Read Replies (1) \| Respond to of 3044

1: Blood. 2003 Dec 11 [Epub ahead of print]. Related Articles, Links Bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Chauhan D, Li G, Podar K, Hideshima T, Shringarpure R, Catley L, Mitsiades C, Munshi N, Tai YT, Suh N, Gribble GW, Honda T, Schlossman R, Richardson P, Sporn MB, Anderson KC. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA. The synthetic triterpenoid 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO) induces apoptosis in leukemic cells. Here we show that CDDO and its new derivative CDDO-Imidazolide (CDDO-Im) trigger apoptosis in multiple myeloma (MM) cells resistant to conventional therapies including melphalan (LR5), doxorubicin (Dox-40), and dexamethasone (MM.1R, U266, RPMI-8226) without affecting the viability of normal cells. CDDO-IM also triggers apoptosis in bone marrow stromal cells (BMSCs) and decreases interleukin-6 (IL-6) secretion induced by MM cell adhesion to BMSCs. Moreover, CDDO-Im-induced apoptosis in MM cells is not blocked by IL-6 or insulin growth factor-1 (IGF-1). Importantly, CDDO-Im and Bortezomib/proteasome inhibitor PS-341 trigger synergistic apoptosis in MM cells associated with loss of mitochondrial membrane potential; Superoxide generation; release of mitochondrial proteins cytochrome-c/Smac, and activation of caspase-8/9/3. Conversely, the pan caspase inhibitor Z-VAD-fmk abrogates the CDDO-Im + Bortezomib-induced apoptosis. Low doses of CDDO-Im and Bortezomib overcomes the cytoprotective effects of anti-apoptotic proteins Bcl2 and Hsp27, as well as NF-kB-mediated growth/survival, and drug-resistance. Finally, combining CDDO-Im and Bortezomib induces apoptosis even in Bortezomib-resistance MM patient cells. Together, these findings provide the framework for clinical evaluation of CDDO-Im, either alone or in combination with Bortezomib, to overcome drug resistance and improve patient outcome in MM.