title: Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma.
abstract: OBJECTIVE
  To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. konnerj@mskcc.org
authors.forename: Jason
authors.initials: J
authors.lastname: Konner
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Grisham
authors.forename: Jae
authors.initials: J
authors.lastname: Park
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
authors.forename: Gillian
authors.initials: G
authors.lastname: Cropp
authors.forename: Robert
authors.initials: R
authors.lastname: Johnson
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Martee L
authors.initials: ML
authors.lastname: Hensley
authors.forename: Paul
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Svetlana
authors.initials: S
authors.lastname: Mironov
authors.forename: Svetlana
authors.initials: S
authors.lastname: Miranov
authors.forename: Samuel
authors.initials: S
authors.lastname: Danishefsky
authors.forename: David
authors.initials: D
authors.lastname: Hyman
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: Jakob
authors.initials: J
authors.lastname: Dupont
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
mesh_terms: D000328:Adult; D000368:Aged; D034261:Epothilones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism; D008297:Male; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D034261:Epothilones; D050257:Tubulin Modulators; C114026:desoxyepothilone B
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