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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

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

Authors: Shingo Miyamoto, Fusanori Yotsumoto, Taeko Ueda, Tatsuya Fukami, Ayako Sanui, Kohei Miyata, Sung Ouk Nam, Satoshi Fukagawa, Takahiro Katsuta, Miyako Maehara, Haruhiko Kondo, Daisuke Miyahara, Kyoko Shirota, Toshiyuki Yoshizato, Masahide Kuroki, Hiroaki Nishikawa, Keijiro Saku, Yoshio Tsuboi, Kenji Ishitsuka, Yasushi Takamatsu, Kazuo Tamura, Akira Matsunaga, Toru Hachisuga, Shinsuke Nishino, Takashi Odawara, Kazuhiro Maeda, Sadao Manabe, Toyokazu Ishikawa, Yoshinobu Okuno, Minako Ohishi, Tomoya Hikita, Hiroto Mizushima, Ryo Iwamoto, Eisuke Mekada

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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/m2 BK-UM is recommended for subsequent clinical trials.

Trial registration

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.
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Literature
1.
Tan DS, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol. 2006;7:925–34.CrossRefPubMed
2.
Crawford SC, Vasey PA, Paul J, Hay A, Davis JA, Kaye SB. Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial. J Clin Oncol. 2005;23:8802–11.CrossRefPubMed
3.
Trimble EL, Wright J, Christan MC. Treatment of platinum-resistant ovarian cancer. Expert Opin Pharmacother. 2001;2:1299–306.CrossRefPubMed
4.
Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16:928–36.CrossRefPubMedPubMedCentral
5.
6.
7.
Goishi K, Higashiyama S, Klagsbrun M, Nakano N, Umata T, Ishikawa M, et al. Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: conversion from juxtacrine to paracrine growth factor activity. Mol Biol Cell. 1995;6:967–80.CrossRefPubMedPubMedCentral
8.
Raab G, Klagsbrun M. Heparin-binding EGF-like growth factor. Biochim Biophys Acta. 1997;1333:F179–99.PubMed
9.
Wang F, Liu R, Lee SW, Sloss CM, Couget J, Cusack JC. Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance. Oncogene. 2007;26:2006–16.CrossRefPubMed
10.
Miyamoto S, Hirata M, Yamazaki A, Kageyama T, Hasuwa H, Mizushima H, et al. Heparin-binding EGF-like growth factor is a promising target for the therapy of ovarian cancer. Cancer Res. 2004;64:5720–7.CrossRefPubMed
11.
Tanaka Y, Miyamoto S, Yagi H, Sonoda K, Kobayashi H, Kishikawa T, et al. Clinical significance of heparin-binding epidermal growth factor-like growth factor and a disintegrin and metalloprotease 17 expression in human ovarian cancer. Clin Cancer Res. 2005;11:4783–92.CrossRefPubMed
12.
Yagi H, Miyamoto S, Tanaka Y, Sonoda K, Kobayashi H, Kishikawa T, et al. Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer. Br J Cancer. 2005;92:1737–45.CrossRefPubMedPubMedCentral
13.
Yagi H, Yotsumoto F, Miyamoto S. Heparin-binding epidermal growth factor-like growth factor promotes transcoelomic metastasis in ovarian cancer through epithelial-mesenchymal transition. Mol Cancer Ther. 2008;7:3441–51.CrossRefPubMed
14.
Miyamoto S, Yagi H, Yotsumoto F, Kawarabayashi T, Mekada E. Heparin-binding epidermal growth factor-like growth factor as a novel targeting molecule for cancer therapy. Cancer Sci. 2006;97:341–7.CrossRefPubMed
15.
Yotsumoto F, Yagi H, Suzuki SO, Oki E, Tsujioka H, Hachisuga T, et al. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophy Res Commun. 2008;365:555–61.CrossRef
16.
Mitamura T, Higashiyama S, Taniguchi N, Klagsbrun M, Mekada E. Diphtheria toxin binds to the epidermal growth factor (EGF)-like domain of human heparin-binding EGF-like growth factor/diphtheria toxin receptor and inhibits specifically its mitogenic activity. J Biol Chem. 1995;270:1015–9.CrossRefPubMed
17.
Kageyama T, Ohishi M, Miyamoto S, Mizushima H, Iwamoto R, Mekada E. Diphtheria toxin mutant CRM197 possesses weak EF2-ADP-ribosyl activity that potentiates its anti-tumorigenic activity. J Biochem. 2007;142:95–104.CrossRefPubMed
18.
Hamaoka M, Chinen I, Murata T, Takashima S, Iwamoto R, Mekada E. Anti-human HB-EGF monoclonal antibodies inhibiting ectodomain shedding of HB-EGF and diphtheria toxin binding. J Biochem. 2010;148:55–69.CrossRefPubMed
19.
20.
Buzzi S, Rubboli D, Buzzi G, Buzzi AM, Morisi C. CRM197 (nontoxic diphtheria toxin): effects on advanced cancer patients. Cancer Immunol Immunother. 2004;53:1041–8.CrossRefPubMed
21.
Nam SO, Yotsumoto F, Miyata K, Suzaki Y, Yagi H, Odawara T, et al. Pre-clinical study of BK-UM, a novel inhibitor of HB-EGF, for ovarian cancer therapy. Anticancer Res. 2014;34:4615–20.PubMed
22.
Hikita S, Yotsumoto F, Fukami T, Horiuchi S, Sanui A, Miyata K, et al. Assessment of HB-EGF levels in peritoneal fluid and serum of ovarian cancer patients using ELISA. Anticancer Res. 2011;31:2553–9.PubMed
23.
Sarantopoulos J, Mita MM, Birrer MJ, Cranmer LD, Campos LT, Zhang X, et al. Phase 1 study of monotherapy with khk2866, an anti-heparin-binding epidermal growth factor-like growth factor monoclonal antibody, in patients with advanced cancer. Target Oncol. 2016;11:317–27.CrossRefPubMed
24.
Zivanovic O, Abramian A, Kullmann M, Fuhrmann C, Coch C, Hoeller T, et al. HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer. Int J Cancer. 2015;136:699–708.PubMed
25.
Kasai N, Adachi M, Yamano K. Preclinical pharmacokinetics evaluation of anti-heparin-binding EGF-like growth factor (HB-EGF) monoclonal antibody using cynomolgus monkeys via 89Zr-immuno-PET study and the determination of drug concentrations in serum and cerebrospinal fluid. Pharm Res. 2016;33:476–86.CrossRefPubMed
26.
Koshikawa N, Mizushima H, Minegishi T, Eguchi F, Yotsumoto F, Nabeshima K, et al. Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells. Cancer Sci. 2011;102:111–6.CrossRefPubMed
Metadata
Title
BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study
Authors
Shingo Miyamoto
Fusanori Yotsumoto
Taeko Ueda
Tatsuya Fukami
Ayako Sanui
Kohei Miyata
Sung Ouk Nam
Satoshi Fukagawa
Takahiro Katsuta
Miyako Maehara
Haruhiko Kondo
Daisuke Miyahara
Kyoko Shirota
Toshiyuki Yoshizato
Masahide Kuroki
Hiroaki Nishikawa
Keijiro Saku
Yoshio Tsuboi
Kenji Ishitsuka
Yasushi Takamatsu
Kazuo Tamura
Akira Matsunaga
Toru Hachisuga
Shinsuke Nishino
Takashi Odawara
Kazuhiro Maeda
Sadao Manabe
Toyokazu Ishikawa
Yoshinobu Okuno
Minako Ohishi
Tomoya Hikita
Hiroto Mizushima
Ryo Iwamoto
Eisuke Mekada
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3071-5

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