Abstract
BackgroundBK-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.MethodsEleven 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.ResultsEight 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.ConclusionsBK-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 registrationThis 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.
Highlights
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)
Most patients with recurrent ovarian cancer (OC) experience massive ascites and ileus associated with transcoelomic metastasis, and preventing transcoelomic metastasis may play a key role in improving the prognosis in OC patients
Eight patients completed the study according to the protocol, one patient withdrew their consent as noted above, and two patients dropped out of the trial because of dose-limiting toxicity (DLT)
Summary
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). 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. Ovarian cancer (OC) is a lethal gynecologic malignancy that has an extremely poor prognosis, due to the extension of OC cells into the peritoneal cavity [1]. Most patients with recurrent OC experience massive ascites and ileus associated with transcoelomic metastasis, and preventing transcoelomic metastasis may play a key role in improving the prognosis in OC patients. In the International Collaborative Ovarian Neoplasm 7 trial, standard chemotherapy with bevacizumab failed to increase overall survival in patients with newly diagnosed OC, but did improve progression-free survival and retention of peritoneal fluid [4]. Platinum is recognized as a key drug for OC therapy [5], and the development of biological agents and molecular-targeted therapeutics with low toxicity are needed to overcome resistance or restore sensitivity to platinum
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