title: Phase I dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors.
abstract: OBJECTIVE
  First-in-man study of KOS-1584, a second generation epothilone.
  
  
  METHODS
  Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized.
  
  
  RESULTS
  Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m(2). Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m(2). At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m(2), 327 ± 161 L/m(2), and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m(2). Two patients achieved partial responses and 24 patients had stable disease (SD).
  
  
  CONCLUSIONS
  The RP2D of KOS-1584 is 36 mg/m(2). The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210-1240, USA.
authors.forename: Elaine T
authors.initials: ET
authors.lastname: Lam
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Cropp
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zhou
authors.forename: Barbara
authors.initials: B
authors.lastname: McCracken
authors.forename: Brandi I
authors.initials: BI
authors.lastname: Haley
authors.forename: Robert G
authors.initials: RG
authors.lastname: Johnson
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D018771:Arthralgia / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D034261:Epothilones; C570748:KOS-1584; D050257:Tubulin Modulators