title: A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.
abstract: This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan).
  
  
  
  Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2.
  
  
  
  Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment.
  
  
  
  The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA. howard.burris@scresearch.net.|Tennessee Oncology, PLLC, Nashville, TN, USA. howard.burris@scresearch.net.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA.|Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: F
authors.initials: F
authors.lastname: Anthony Greco
authors.affiliation: Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Thompson
authors.affiliation: Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Barton
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA.|Tennessee Oncology, PLLC, Nashville, TN, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Nippon Kayaku Co., Ltd, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nambu
authors.affiliation: Nippon Kayaku Co., Ltd, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA.
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008823:Micelles; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D004337:Drug Carriers; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D008823:Micelles; D011108:Polymers; D000099148:UGT1A1 Enzyme
keywords: Dose escalation; Macromolecular polymeric micelle; Pharmacokinetics; SN-38