title: A phase 1 study of KOS-862 (Epothilone D) co-administered with carboplatin (Paraplatin®) in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies.
  
  
  METHODS
  Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m(2))/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3 + 3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied.
  
  
  RESULTS
  Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m(2) + carboplatin AUC = 6.
  
  
  CONCLUSIONS
  The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations.
authors.affiliation: Ohio State University, Columbus, OH, USA. paul.monk@osumc.edu
authors.forename: J Paul
authors.initials: JP
authors.lastname: Monk
authors.forename: Miguel
authors.initials: M
authors.lastname: Villalona-Calero
authors.forename: Joe
authors.initials: J
authors.lastname: Larkin
authors.forename: Greg
authors.initials: G
authors.lastname: Otterson
authors.forename: David S
authors.initials: DS
authors.lastname: Spriggs
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Cropp
authors.forename: Robert G
authors.initials: RG
authors.lastname: Johnson
authors.forename: Martee L
authors.initials: ML
authors.lastname: Hensley
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D016190:Carboplatin; C114026:desoxyepothilone B