BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study.
BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study.
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DOI：
10.1186/s12885-017-3071-5
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发表时间：
2017-01-31
期刊：
影响因子：
3.8
通讯作者：
Mekada E
中科院分区：
文献类型：
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作者：
Miyamoto S;Yotsumoto F;Ueda T;Fukami T;Sanui A;Miyata K;Nam SO;Fukagawa S;Katsuta T;Maehara M;Kondo H;Miyahara D;Shirota K;Yoshizato T;Kuroki M;Nishikawa H;Saku K;Tsuboi Y;Ishitsuka K;Takamatsu Y;Tamura K;Matsunaga A;Hachisuga T;Nishino S;Odawara T;Maeda K;Manabe S;Ishikawa T;Okuno Y;Ohishi M;Hikita T;Mizushima H;Iwamoto R;Mekada E
BK-UM（CRM 197）是白喉毒素的突变形式，是肝素结合表皮生长因子样生长因子（HB-EGF）的特异性抑制剂。我们评估了BK-UM在复发性卵巢癌（OC）或腹膜癌（PC）患者中的安全性、药代动力学、推荐剂量和疗效，并测定了BK-UM给药后血清和腹腔液中的HB-EGF水平。11例晚期或复发性OC或PC患者入组并通过腹腔途径接受BK-UM治疗。采用3 + 3设计递增剂量（1.0、2.0、3.3和5.0 mg/m2）。11例患者中有8例完成治疗。在剂量水平1（1.0 mg/m2）和2（2.0 mg/m2）下未发生剂量限制性毒性（DLT）。在剂量水平3（3.3 mg/m2）的4例患者中，有2例观察到3级一过性低血压不良事件（在本研究中定义为DLT）。BK-UM治疗与血清和腹腔液中HB-EGF水平的降低相关，分别为11例患者中的7例和8例患者中的5例。临床结局包括1例患者部分缓解，5例患者病情稳定，5例患者病情进展。BK-UM在1.0和2.0 mg/m2剂量下耐受性良好，有证据表明在复发性OC或PC患者中具有临床疗效。建议后续临床试验使用2.0 mg/m2 BK-UM。本试验是作为一项药物启动的临床试验进行的前瞻性研究。试验编号为UMIN 000001002和UMIN 000001001，注册日期分别为1/30/2008和2/4/2008。UMIN 000001001注册为UMIN 000001002后BK-UM持续给药的试验。本文的在线版本（doi：10.1186/s12885-017-3071-5）包含补充材料，可供授权用户使用。
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/m2 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. The online version of this article (doi:10.1186/s12885-017-3071-5) contains supplementary material, which is available to authorized users.