title: NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis.
abstract: This study was an open-label phase I study to confirm the safety and tolerability of NC-6004 in combination with gemcitabine in Japanese patients with advanced solid tumors and to assess the PK effects of NC-6004 monotherapy.
  
  
  
  This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) and recommended dose of NC-6004 combined with gemcitabine. Safety and pharmacokinetics were assessed. The administration of NC-6004 alone was started at 60 mg/m2every treatment cycle (21 days per cycle). From the second through eighth cycles, patients received NC-6004 in combination with 1000 mg/m2of gemcitabine that was administered on day 1 and day 8 of each cycle, except for the first treatment cycle.
  
  
  
  Twelve patients with advanced solid tumors received 60 or 90 mg/m2NC-6004. Both MTD and RD were determined to be 90 mg/m2. The most common drug-related adverse events were neutrophil decrease (66.7%) and white blood cell count decrease (41.7%). Population pharmacokinetic (PK) analysis revealed that NC-6004 PK profile in Japanese study was not significantly different from that in a previous Caucasian study.
  
  
  
  Both MTD and RD of NC-6004 were determined to be 90 mg/m2. The pharmacodynamic (PD) model well explained the time course of estimated glomerular filtration rate (eGFR) and amplitude of decrease in eGFR. The decrease in eGFR appeared to reach saturation at >100 mg/m2with NC-6004. Estimated probability of acute kidney injury on this PK/PD simulation was 30% with NC-6004 and 70% with cisplatin, which may better explain the renal toxicity profile.
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwasa
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: NanoCarrier Co. Ltd., Onoya Kyobashi Building, 1-4-10 Kyobashi, Chuo-ku, Tokyo, 104-0031, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Harada
authors.affiliation: NanoCarrier Co. Ltd., Onoya Kyobashi Building, 1-4-10 Kyobashi, Chuo-ku, Tokyo, 104-0031, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Naito
authors.affiliation: NanoCarrier Co. Ltd., Onoya Kyobashi Building, 1-4-10 Kyobashi, Chuo-ku, Tokyo, 104-0031, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: NanoCarrier Co. Ltd., Onoya Kyobashi Building, 1-4-10 Kyobashi, Chuo-ku, Tokyo, 104-0031, Japan. masada@nanocarrier.co.jp.
authors.forename: Atsuhiro
authors.identifier: 0000-0002-6158-9459
authors.initials: A
authors.lastname: Masada
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010984:Platinum / Q000097:blood; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D044465:White People; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D011099:Polyglutamic Acid; D010984:Platinum; C557897:demplatin pegraglumer; D002945:Cisplatin; D000093542:Gemcitabine
keywords: Acute kidney injury; Cisplatin; Micelles; NC-6004; Population PK/PD analysis