BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study

• Published in: BMC cancer Vol. 17; no. 1; p. 89
• Main Authors: Miyamoto, Shingo, Yotsumoto, Fusanori, Ueda, Taeko, Fukami, Tatsuya, Sanui, Ayako, Miyata, Kohei, Nam, Sung Ouk, Fukagawa, Satoshi, Katsuta, Takahiro, Maehara, Miyako, Kondo, Haruhiko, Miyahara, Daisuke, Shirota, Kyoko, Yoshizato, Toshiyuki, Kuroki, Masahide, Nishikawa, Hiroaki, Saku, Keijiro, Tsuboi, Yoshio, Ishitsuka, Kenji, Takamatsu, Yasushi, Tamura, Kazuo, Matsunaga, Akira, Hachisuga, Toru, Nishino, Shinsuke, Odawara, Takashi, Maeda, Kazuhiro, Manabe, Sadao, Ishikawa, Toyokazu, Okuno, Yoshinobu, Ohishi, Minako, Hikita, Tomoya, Mizushima, Hiroto, Iwamoto, Ryo, Mekada, Eisuke
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.01.2017; BioMed Central
• Subjects: Aged; Bacterial Proteins - administration & dosage; Bacterial Proteins - pharmacokinetics; Care and treatment; Diphtheria toxin; Dose-Response Relationship, Drug; Epidermal growth factor; Female; Heparin-binding EGF-like Growth Factor - metabolism; Humans; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - metabolism; Japan; BK-UM; Phase-I study; HB-EGF; Targeted therapy; Ovarian cancer
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-017-3071-5

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/m ) 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/m ) and 2 (2.0 mg/m ). 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/m ). 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/m , with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0 mg/m BK-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 .