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Biotech / Medical : Indications -- Cancer -- Ignore unavailable to you. Want to Upgrade?

To: nigel bates who wrote (65)	5/17/2001 7:47:40 PM
From: nigel bates	Respond to of 1840

Phase I First-in-Man Study of the Epothilone B Analog BMS-247550 in Patients with Advanced Cancer. David Spriggs, Steven Soignet, Brian Bienvenu, Steven Letrent, David Lebwohl, Suzanne Jones, Howard Burris, III, Memorial Sloan-Kettering Cancer Center, New York, NY; Bristol-Myers Squibb PRI, Wallingford, CT; Sarah Cannon Cancer Center, Nashville, TN. Epothilones are a new class of agents which induces tubulin polymerization. Epothilone B analog BMS-247550 demonstrated excellent preclinical activity in taxane-resistant tumor models, including those with MDR overexpression and [beta]-tubulin mutation. We have completed accrual to a Phase I trial of BMS-247550 administered once every 3 weeks as a 1 hour infusion, using an accelerated titration design (Simon et al JNCI/1997). Thirty-one patients (pts) were treated at dose levels of 7.4, 15, 30, 50, 57 and 65 mg/m2. Pharmacokinetics will be reported in a separate abstract. At doses below 50, no DLT was observed. BMS-247550 is formulated in Cremophor-EL, and a hypersensitivity reaction was observed in one pt at 30 mg/m2. HSR was subsequently prevented in all pts with oral H1/H2 blockers. First-course DLT was experienced by 2/ 3 pts at 65 mg/m2 (gr 3 neuropathy and prolonged gr 4 neutropenia; prolonged gr 4 neutropenia) and by all 3 patients at 57 mg/m2 (gr 3 arthralgia and myalgia in 2 pts; gr 4 neutropenia with pneumococcal sepsis and death in 1 pt). After the MTD was established as 50 mg/m2, a cohort of 10 additional pts were treated at this dose. Severe toxicity, requiring a dose reduction, was observed in only one of the these pts (febrile neutropenia). Other toxicities include fatigue, weakness, constipation, diarrhea, nausea, vomiting, rash, alopecia and low-grade neuropathy. ANC nadir was related to exposure via a sigmoid Emax model; additional exposure/toxicity analyses are ongoing. Antitumor activity seen among 22 pts treated at 50 mg/m2 and above includes 1 CR (ovary post-TAXOL), 3 PR (NSCLC post-Taxotere, melanoma in 2 pts), 11 SD and 7 PD or early toxicity; 7 pts continue on treatment. BMS-247550 has toxicity similar to the taxanes and has shown evidence of activity in patients with taxane-resistant and taxane-insensitive tumors.