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

Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA, .
Investigational New Drugs (Impact Factor: 2.92). 11/2011; 30(6). DOI: 10.1007/s10637-011-9765-7
Source: PubMed

ABSTRACT 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/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). Results 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 (½)) = 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. 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/m(2) weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.

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    ABSTRACT: A sensitive, accurate and rugged UHPLC–MS/MS method was developed and validated for the quantitation of Epothilone D (EpoD), a microtubule stabilizer in development for treatment of Alzeimer's disease, in rat plasma. The ester group in EpoD can be hydrolyzed by esterases in blood or plasma, which creates a stability concern for the bioanalysis of EpoD. Species differences in the stability of EpoD in plasma were observed. Carboxylesterases were identified as the likely esterases responsible for the hydrolysis of EpoD in plasma ex vivo, and the cause of the species different stability. Phenylmethanesulfonyl fluoride, a carboxylesterase inhibitor, was used to stabilize EpoD in rat blood during sample collection, processing, and storage. A systematic method screening and optimization strategy was used to improve the assay sensitivity and minimize potential bioanalytical risks. The stabilized plasma samples were extracted by liquid–liquid extraction. Chromatographic separation was achieved on an Acquity UPLC BEH Phenyl column with a gradient elution. EpoD and its stable isotope labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 0.100 to 100 ng/mL was fitted to a 1/x2 weighted linear regression model. The intra-assay precision was within ±3.6% CV and inter-assay precision was within ±4.2% CV. The assay accuracy was within ±8.3% of the nominal values. Assay recovery of EpoD was high (∼90%) and matrix effect was minimal (1.02–1.05). EpoD was stable in stabilized rat plasma for at least 30 h at room temperature, 180 days at −20 °C, and following three freeze-thaw cycles. The validated method was successfully applied to sample analysis in toxicology studies.
    Journal of Chromatography B 10/2014; 969:60-68. DOI:10.1016/j.jchromb.2014.08.006 · 2.73 Impact Factor