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

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 5.0mg/m2) using a 3+3 design. Results: Eight of 11 patients completed treatment. No dose-limiting toxicity (DLT) was experienced at dose levels 1 (1.0mg/m2) and 2 (2.0mg/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 (3.3mg/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 2.0mg/m2, with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0mg/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 UMIN000001002and 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.