title: BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study.
abstract: BK-UM (CRM197) is a mutant form of diphtheria toxin and a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF). We assessed the safety, pharmacokinetics, recommended dose, and efficacy of BK-UM in patients with recurrent ovarian cancer (OC) or peritoneal cancer (PC), and measured HB-EGF levels in serum and abdominal fluid after BK-UM administration.
  
  
  
  Eleven patients with advanced or recurrent OC or PC were enrolled and treated with BK-UM via the intraperitoneal route. The dose was escalated (1.0, 2.0, 3.3, and 5.0 mg/m2) using a 3 + 3 design.
  
  
  
  Eight of 11 patients completed treatment. No dose-limiting toxicity (DLT) was experienced at dose levels 1 (1.0 mg/m2) and 2 (2.0 mg/m2). Grade 3 transient hypotension as an adverse event (defined as a DLT in the present study) was observed in two of four patients at dose level 3 (3.3 mg/m2). Treatment with BK-UM was associated with decreases in HB-EGF levels in serum and abdominal fluid in seven of 11 patients and five of eight patients, respectively. Clinical outcomes included a partial response in one patient, stable disease in five patients, and progressive disease in five patients.
  
  
  
  BK-UM was well tolerated at doses of 1.0 and 2.0 mg/m2, with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0 mg/m2BK-UM is recommended for subsequent clinical trials.
  
  
  
  This trial was prospectively performed as an investigator-initiated clinical trial. The trial numbers are UMIN000001002 and UMIN000001001, with registration dates of 1/30/2008 and 2/4/2008, respectively. UMIN000001001 was registered as a trial for the continuous administration of BK-UM after UMIN000001002 .
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. smiya@cis.fukuoka-u.ac.jp.|Center for Advanced Molecular Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. smiya@cis.fukuoka-u.ac.jp.
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.|Center for Advanced Molecular Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Fusanori
authors.initials: F
authors.lastname: Yotsumoto
authors.affiliation: Department of Obstetrics and Gynecology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Sanui
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.|Center for Advanced Molecular Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Sung Ouk
authors.initials: SO
authors.lastname: Nam
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.|Center for Advanced Molecular Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukagawa
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Katsuta
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Maehara
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miyahara
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shirota
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Kurume University, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoshizato
authors.affiliation: Center for Advanced Molecular Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.|Department of Biochemistry, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Kuroki
authors.affiliation: Department of Cardiology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Department of Cardiology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
authors.affiliation: Department of Neurology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tsuboi
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Medical and Dental Hospital, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious Disease, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takamatsu
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious Disease, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsunaga
authors.affiliation: Department of Obstetrics and Gynecology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hachisuga
authors.affiliation: Kanonji Institute, Research Foundation for Microbial Diseases of Osaka University, 2-9-41 Yahata-Cho, Kanonji, Kagawa, 768-0061, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Nishino
authors.affiliation: Kanonji Institute, Research Foundation for Microbial Diseases of Osaka University, 2-9-41 Yahata-Cho, Kanonji, Kagawa, 768-0061, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Odawara
authors.affiliation: Kanonji Institute, Research Foundation for Microbial Diseases of Osaka University, 2-9-41 Yahata-Cho, Kanonji, Kagawa, 768-0061, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Kanonji Institute, Research Foundation for Microbial Diseases of Osaka University, 2-9-41 Yahata-Cho, Kanonji, Kagawa, 768-0061, Japan.
authors.forename: Sadao
authors.initials: S
authors.lastname: Manabe
authors.affiliation: Kanonji Institute, Research Foundation for Microbial Diseases of Osaka University, 2-9-41 Yahata-Cho, Kanonji, Kagawa, 768-0061, Japan.
authors.forename: Toyokazu
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Kanonji Institute, Research Foundation for Microbial Diseases of Osaka University, 2-9-41 Yahata-Cho, Kanonji, Kagawa, 768-0061, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Disease, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Ohishi
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Disease, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.|Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hikita
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Disease, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Mizushima
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Disease, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Disease, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Mekada
mesh_terms: D000368:Aged; D001426:Bacterial Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D066257:Heparin-binding EGF-like Growth Factor; C028581:CRM197 (non-toxic variant of diphtheria toxin)
keywords: BK-UM; HB-EGF; Ovarian cancer; Phase-I study; Targeted therapy