cabozantinib and Adenocarcinoma--Clear-Cell

To evaluate the efficacy and tolerability of cabozantinib in recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer.. Patients with recurrent ovarian, fallopian or primary peritoneal tumors with at least 50% clear cell histomorphology, measurable disease, one or two prior regimens and ECOG performance status 0-2 received cabozantinib 60 mg orally once daily continuously, in 4-week cycles until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) at six months and complete or partial tumor response (as assessed by RECIST 1.1). Secondary endpoints included toxicity, PFS, and overall survival (OS).. Over 19 months, 13 patients were accrued. Fifty-four percent of patients were ≥60 years of age. Performance statuses of 0 and 1 comprised 8 and 5 patients. No objective tumor responses were seen. Three (23% [95% CI: 5%, 54%]) of 13 patients had PFS ≥6 months, including one patient who received cabozantinib for 23 cycles and was still on treatment as of the data cut-off date. Median PFS and OS were 3.6 and 8.1 months, respectively. There was one patient with a grade 5 event: a thromboembolic event considered possibly related to study therapy; patient's cause of death was determined to be due to disease and protocol treatment. Four other patients had thromboembolic events (two grade 3 and one each grade 1 and grade 2). Other grade 3 or higher events reported in two or more patients were nausea, vomiting, fatigue, dyspnea, and dehydration.. Cabozantinib demonstrated minimal activity in the second- and third-line treatments of clear cell ovarian, fallopian tube or primary peritoneal carcinoma.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Anilides; Fallopian Tube Neoplasms; Female; Humans; Middle Aged; Ovarian Neoplasms; Peritoneal Neoplasms; Pyridines

Topics: Adenocarcinoma, Clear Cell; Anilides; Female; Humans; Ovarian Neoplasms; Pyridines; Receptor Protein-Tyrosine Kinases

Several reports have shown that the overexpression of the MET proto-oncogene, receptor tyrosine kinase (MET), was more frequently observed in clear cell carcinoma (CCC) than in non-CCC. We evaluated the antitumor activity of cabozantinib, that targets MET.. A gene expression analysis of tumors from human ovarian cancers was carried out by transcriptome sequencing. An in vitro 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay (MTT assay) and in vivo experiments were performed to determine the activity of cabozantinib.. The MET levels were higher in tumors with CCC than high-grade serous carcinoma (2.2-fold). Cabozantinib inhibited cell viability and phosphorylation of AKT and MAPK under the treatment of hepatocyte growth factor in RMG-I CCC cells. The tumors removed from mice given cabozantinib of 10 mg/kg weighed 70% less than control on day 15, and the immunohistochemical reactivity of phosphorylated MET was reduced compared with control mice.. Cabozantinib contributes to tumor reduction, and phosphorylated MET represents an attractive target of CCC.

Topics: Adenocarcinoma, Clear Cell; Anilides; Animals; Apoptosis; Cell Proliferation; Female; Humans; In Vitro Techniques; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Tumor Cells, Cultured; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays