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- W2956201544 abstract "2571 Background: KOS-1584 is an epothilone with increased potency and improved pharmacologic profile (enhanced water solubility, tumor penetration and reduced CNS exposure). Methods: Define the MTD, toxicity, PK, pharmacodynamics (PD), and early activity of KOS-1584 when administered to pts with advanced malignancies via 1-hr infusion on one of 2 schedules: Days 1, 8 & 15 every 4 weeks and Days 1 & 8 every 3 weeks. PD: assessed by serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot. Methods: 37 pts enrolled in 10 cohorts (0.8 - 25 mg/m 2 ) on the 4-week schedule (22 F; median age/ECOG/prior regimens of 56, 1 and 4, respectively). One pt has been enrolled at 16 mg/m 2 on the 3-week schedule. For the 4-week schedule: DLTs were observed at 20 and 25 mg/m 2 ; the 16 mg/m 2 cohort is being expanded (using antidiarrheal prophylaxis). All episodes of DLT except 1 involved diarrhea with increasing severity after successive infusions despite maximal supportive care; 1 pt had typhlitis upon biopsy. An ovarian cancer pt experienced DLT consisting of Grade 3 weakness, neutropenia and peripheral sensory neuropathy (this pt had high plasma drug concentrations, possibly related to pre-existing severe hypoalbuminemia and ascites). Common all-grade drug- related toxicities (n=37): nausea (51%), diarrhea, fatigue (both 49%), vomiting (32%), anorexia (24%), constipation (24%), peripheral sensory neuropathy (19%) and anemia (16%). Neutropenia/leucopenia (Grade 1–2) observed at 16–25 mg/m 2 dose levels. Except for the DLT involving peripheral neurotoxicity, all neurotoxicity was mild-to-moderate. PK (n=37): t½ 28.1 ± 8.7, Vz 627 ± 291 L, CL 18.0 ± 8.3 L/h. C max /AUC (25 mg/m 2 ): 1,069 ± 2,456 ng/mL, 3,764 ± 2,579 ng/mL*h. Dose proportional increase in AUC and C max observed. ↑polymerized microtubules observed with maximal effect at end of infusion. Antitumor activity: NSCLC (1pt: confirmed PR; 10 cycles), ovarian cancer (1pt: 40% ↓CA125; 6 cycles), and H&N (1 pt: SD), these pts had all received doses ≥ 7.5 mg/m 2 . Conclusions: Accrual continues to define the optimal dose on both schedules; use of aggressive anti-diarrheal prophylaxis has been implemented. No significant financial relationships to disclose." @default.
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- W2956201544 date "2007-06-20" @default.
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- W2956201544 title "Phase I trial of KOS-1584 (a novel epothilone) using two weekly dosing schedules" @default.
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