Abstract

2024 Background: Similar to taxanes, epothilones are a class of naturally occurring cytotoxic macrolides that stabilize microtubules and induce mitotic arrest, retaining potency in P-glycoprotein MDR cell lines. 6 schedules of KOS-862 were investigated in phase I trials. Methods: As the optimal schedule in the mouse xenograft model used prolonged exposure (6-hr IV infusion at 30 mg/kg) to reach plasma steady state Css=425 ng/mL, two CI schedules were attempted: a 24-hr CI (Schedule A) and up to 72-hr CI (Schedule B) q 2 weeks. Steady state is difficult to maintain for a drug with a rapid alpha distribution, hence a loading dose (75 mg/hr for 30 min) was incorporated, followed by maintenance dose. Results: 24 pts have been enrolled (median age 62 yrs, range 28–86 yrs; 7 F/17 M; median KPS 80; median prior regimens 3, range 0–10): 17 on Schedule A, 7 on Schedule B. Eighty total infusions have been administered. 4 dose levels have been tested on Schedule A (1, 2, 4 and 6 mg/hr rates); 2 dose levels on Schedule B (1 and 1.7 mg/hr). Drug-related toxicity includes mild-to-moderate fatigue, nausea/abdominal pain, dizziness, and neurosensory. One episode of grade 3 neurosensory occurred at 6 mg/hr x 24-hr CI; this dose group is being expanded. AUC=Css(SD) at this dose was 12300 ng/mL*h; constant dosing at 7 mg/h for 23.5 h would theoretically achieve a Css=423 ng/mL (Css=AUCSDτ n →τ n+1 /τ ). Pts dosed at 4 mg/h for 23.5h achieved Css=200 ng/mL. Comparison of PK between short infusion and CI showed similar results (mean±SD) CL=6.7±2.7 v 8.7±2.9 L/h/m2; half-life 10.3±2.9 v 10.8±2.3 hours; Vz 96±41 v136±59 L/m2; MRT 10.0±3.6 v 17.1±4.5 hours. As a marker of biologic activity, PBMCs were examined for microtubule bundle formation at the end of the CI. On Schedule A, 15 and 20% bundle formation at 4 and 6 mg/h was observed, respectively, indicating that there was significant polymerization over this period of time. Signs of antitumor activity included 1 pt with bladder ca (shrinkage of primarily nodal disease) and 1 pt with prostate ca (25% decline in PSA). Conclusions: Biologic activity at tolerable doses has been noted and accrual continues to define the recommended dose. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kosan Biosciences, Inc. Kosan Biosciences, Inc. Kosan Biosciences, Inc. Kosan Biosciences, Inc. Kosan Biosciences, Inc.

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