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

摘要

To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma.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/m(2)). 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/m(2).Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m(2). PK data were linear from 16 to 100 mg/m(2), with proportional increases in mean C(max) and AUC(tot) as a function of dose. Full PK analysis (mean?±?SD) at 100 mg/m(2) revealed the following: half-life (t (?))?=?9.1?±?2.2 h; volume of distribution (V(z))?=?119?±?41 L/m(2); clearance (CL)?=?9.3?±?3.2 L/h/m(2). 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/m(2). 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.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/m(2) weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.