cabozantinib and Ovarian-Neoplasms

Cabozantinib is a receptor tyrosine kinases inhibitor that targets MET (c-MET), VEGF receptor 2 (VEGFR2), RET, AXL, KIT, FLT-3, and TIE-2 and previously showed promising single agent activity in recurrent ovarian cancer.. This was an open label, 1:1 randomized study of cabozantinib 60 mg orally (PO) daily versus weekly paclitaxel 80 mg/m. Median PFS was similar for both treatment groups and was 5.3 months for cabozantinib and 5.5 months for weekly paclitaxel (HR 1.11 (90% CI 0.77-1.61, p = 0.64)). Secondary analyses of overall survival (OS) and event free survival (EFS) showed that cabozantinib did not perform as well as weekly paclitaxel. Median OS for cabozantinib was 19.4 months and was not reached for weekly paclitaxel (HR 2.27 (90% CI 1.17-4.41, p = 0.04). EFS was also worse in the cabozantinib arm, 3.5 months, compared to weekly paclitaxel at 5.0 months (HR 1.81 (90% CI 1.24-2.63, p = 0.01). Overall response rate (ORR) was less for cabozantinib compared to weekly paclitaxel (7% versus 24.1%). Gastrointestinal toxicities, specifically nausea, diarrhea, and abdominal pain were worse in the cabozantinib arm.. Median PFS was similar for cabozantinib and weekly paclitaxel. However, OS, EFS, and ORR were worse for cabozantinib compared to weekly paclitaxel. Cabozantinib given at this dose and schedule cannot be recommended as a treatment for recurrent ovarian cancer.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents, Phytogenic; Carcinoma, Ovarian Epithelial; Drug Administration Schedule; Fallopian Tube Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Protein Kinase Inhibitors; Pyridines

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

Cabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types.. Patients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment.. Seventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks.. Cabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions.. This trial is registered at ClinicalTrial.gov (NCT00940225).

Topics: Adult; Aged; Anilides; Antineoplastic Agents; Carcinoma; Female; Humans; Middle Aged; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyridines; Survival Analysis

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

Glycogen synthase kinase 3β (GSK 3β) is a highly conserved serine/threonine kinase, and its roles in cancer remain controversial. Cumulative evidence supported that GSK 3β inhibitors could suppress ovarian cancer (OC) development in vitro and made a new direction for ovarian cancer treatment. Here, we reported a series of novel substituted benzothiazinones as non-ATP competitive inhibitors of GSK 3β. Further studies showed that most of them had antiproliferative activities in ovarian cancer cell lines in vitro. As the most promising candidate of them, compound 20g induced cells apoptosis, arrested the cell cycle at the G1 phase in the A2780 cell line and showed moderate suppression efficacy in a female BALB/C nude mice model. All of the results demonstrated that compound 20g, as the first reported non-ATP competitive small molecule inhibitor of GSK 3β with suppression efficacy on ovarian cancer both in vitro and in vivo, might represent a potential candidate for the treatment of OC.

Topics: Animals; Benzothiazoles; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Discovery; Female; Glycogen Synthase Kinase 3 beta; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Ovarian Neoplasms; Protein Kinase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured

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