Purpose: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks.Experimental Design: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550.Results: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m 2 . At 50 mg/m 2 , 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m 2 (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m 2 , the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m 2 . Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naïve breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively)
The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m2 over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.
PTSD is associated with increased regional blood flow in limbic areas and the right temporal and parietal cortex compared with age-matched normal volunteers.
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