Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma

Purpose To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. Patients and Methods Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16–120 mg/m2). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m2. Results Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m2. PK data were linear from 16 to 100 mg/m2, with proportional increases in mean Cmax and AUCtot as a function of dose. Full PK analysis (mean ± SD) at 100 mg/m2 revealed the following: half-life (t ½) = 9.1 ± 2.2 h; volume of distribution (Vz) = 119 ± 41 L/m2; clearance (CL) = 9.3 ± 3.2 L/h/m2. MTBF (n = 9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m2. Tumor shrinkage (n = 2, lymphoma), stable disease >3 months (n = 5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n = 1, colorectal cancer/CEA) were observed. Conclusion KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m2 weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.