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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3071-5) contains supplementary material, which is available to authorized users.

Serum Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) as a Biomarker for Primary Ovarian Cancer

“…HB-EGF-targeted agents have been tested in two phase I clinical trials, which investigated the safety, tolerability, and efficacy of the inhibitory monoclonal antibody to HB- EGF KHK2866 in patients with advanced ovarian cancer and of BK-UM in patients with recurrent ovarian cancer (21,23). Companion diagnostics for each agent were also developed (8,24).…”

“…Companion diagnostics for each agent were also developed (8,24). The studies found that serum HB-EGF levels were reduced by intravenous injection of KHK2866 (23), and significantly reduced by intraperitoneal administration of BK-UM in patients with high levels of serum HB-EGF (>125 pg/ml by ELISA) (21). However, the KHK2866 antibody caused reversible neuropsychiatric toxicity and its development has been discontinued (23).…”

“…However, the KHK2866 antibody caused reversible neuropsychiatric toxicity and its development has been discontinued (23). However, the trial of BK-UM showed not only that it was safe and tolerable, but also that high serum HB-EGF concentrations were associated with poor clinical prognosis (21). These data suggest that patients with high serum HB-EGF levels could be good candidates for HB-EGF-targeted therapy.…”

“…Addition of CRM197 reduced production of HB-EGF by a variety of cancer cells in culture, and strongly inhibited the growth of several types of cancer in nude mice (17)(18)(19). In clinical trials, CRM197 injected subcutaneously in the abdominal wall or administered intraperitoneally to patients with recurrent ovarian cancer was safe and relatively well tolerated (20,21). Because administration of CRM197 is expected to inhibit the expression of HB-EGF in cancer cells, it is important to identify the clinical features of patients with ovarian cancer who have high serum HB-EGF levels and thus might benefit most from CRM197 therapy.…”

HB-EGF Is A Promising Therapeutic Target for Lung Cancer with Secondary Mutation of EGFRT790M

“…Conversely, the blockage of HB-EGF can inhibit both HB-EGF-dependent homodimerization and heterodimerization, demonstrating that an inhibitor of HB-EGF suppresses AKT signaling as well as ERK. CRM197, an inhibitor of HB-EGF, and an anticancer agent with a high molecular weight, was shown to be clinically safe and effective for patients with ovarian cancer (23). The combination of TKIs and CRM197 may be a potential treatment for patients with NSCLC with EGFR mutation.…”