A phase I pharmacokinetic (PK) study of the Epothilone B analogue, ixabepilone (BMS-247550) in patients (pts) with advanced malignancies and varying degrees of hepatic impairment. A SWOG Early Therapeutics Committee and NCI Organ Dysfunction Working Group Trial

2004 Background: Ixabepilone (Ix) is a semisynthetic Epothilone B derivative with antitumor activity in breast cancer pts previously treated with taxanes and in chemotherapy naïve prostate cancer pts. Because Ix is hepatically metabolized, the following study was performed to define dosing recommendations for pts with varying degrees of hepatic impairment. Methods: Pts were classified into hepatic dysfunction cohorts defined by a modified NCI Organ Dysfunction Working Group (NCI) schema. Starting doses were escalated in new pts independently in each cohort using a standard phase I design. Results: Overall, 71 pts were registered and 66 pts are evaluable for cycle 1 dose limiting toxicities (DLTs). Ix was administered at 10–40 mg/m2 as 10 minute infusions q3wks. Dose levels reached 40, 40, 30, and 20 mg/m2 for pts in Groups A, B, C and D, respectively. In group B, DLTs were observed in 2/12 pts treated at 30 mg/m2 (febrile neutropenia, grade (gr)3 mucositis, and gr3 diarrhea) and 3/8 pts at 40 mg/m2 (febrile neutropenia, gr3 nausea/vomiting, gr3 hyponatremia). In group C, DLTs were observed in 2/10 pts at 20 mg/m2 (gr3 dehydration, gr3 muscle weakness) and 2/3 pts at 30 mg/m2 (febrile neutropenia, gr 4 neutropenia). In group D, DLTs were observed in 2/9 pts at 10 mg/m2 (gr3 infection and gr3 renal failure) and 1/5 pts treated at 20 mg/m2 (gr3 infection). Otherwise, Ix was generally well tolerated. Pharmacokinetic parameters are currently being analyzed. No objective responses have been documented. Conclusions: Ix dose reduction is required in pts with moderate to severe liver dysfunction. The recommended Ix dose for group C patients is 30 mg/m2. To define the impact of mild liver impairment, Group B has been stratified further into B1 (Bili ≤ ULN and AST > ULN) and B2 (ULN < Bili ≤ 1.5 × ULN, AST any). Accrual continues to groups B1 and B2 at 40 mg/m2 and group D at 20 mg/m2. [Table: see text] [Table: see text]