Clinical Trial Investigating Pazopanib in Patients With Platinum-resistant Advanced Ovarian Cancer

Ovarian cancer is considered a chemo-responsive neoplasm, with initial response rates to systemic chemotherapy exceeding 80% when integrated with primary cytoreductive surgery Despite this, over 50% of women diagnosed with epithelial ovarian cancer eventually go on to die from their disease. Six major trials published over the past 15 years report that the median PFS for patients with advanced disease ranges between 16 and 23 months while the median OS lies between 31 and 65 months.The majority of patients who achieve a Complete Response with first-line chemotherapy ultimately develop recurrent disease. These patients can be subdivided into platinum-sensitive or platinum-resistant groups. In platinum-sensitive patients, disease recurrence occurs more than 6 months after cessation of initial platinum-containing chemotherapy. Platinum-based therapies are typically used to retreat these patients, in light of clinically meaningful responses observed in these patients following a second platinum-based treatment.Currently, there is no optimal treatment strategy for platinum-resistant patients whose disease recurs within 6 months of completing initial platinum-based chemotherapy.Despite a wide range of available treatments, prolonged survival has not been shown in this setting, and ORR is generally less than 20%. As resistant-disease is not curable, the goals of treatment for these patients include palliation of symptoms and improvements in quality of life. Platinum-resistance is therefore a significant clinical problem for which improved treatment regimens are needed. In this regard, molecular targeted therapeutic agents herald a new era for cancer treatment. In the setting of epithelial ovarian cancer, a growing body of evidence supports the use of anti-angiogenic agents.Platinum-resistant ovarian cancer patients are often treated with sequential lines of single-agent chemotherapy. Commonly used agents include topotecan, pegylated liposomal doxorubicin (PLD), weekly paclitaxel and gemcitabine.Topotecan is topoisomerase I inhibitor well established as therapy for recurrent ovarian cancer, with demonstrated efficacy in platinum-resistant populations. PLD is licensed in the US and Europe for use in ovarian cancer after failure of platinum chemotherapy and is recommended by the NCCN as a treatment option in this setting. PLD and topotecan have been compared in a Phase III study of 474 patients with tumours that were recurrent or refractory to platinum-based chemotherapy. In the subgroup of patients with platinum-resistant tumours treated with PLD (n=130), the ORR was 12.3%, and median PFS and OS were 2.1 and 8.2 months, respectively. The 124 platinum-resistant patients who received topotecan achieved median PFS and OS of 3.1 months and 9.5 months, respectively, which were not significantly different from the PLD group. For platinum-resistant patients, outcomes were not significantly different between treatment groups so whatever treatment option is acceptable.In a recent study in platinum-resistant recurrent ovarian cancer patients, topotecan monotherapy showed and ORR of 19% and 9% when used as conventional or weekly schedule, respectively. Angiogenesis is known to play a critical role in the growth of ovarian tumours and may represent an important target. For example, several studies have demonstrated that increased microvessel density in primary ovarian tumours is associated with VEGF expression and predicted worsened survival rates. Likewise, circulating VEGF levels were significantly higher in ovarian cancer subjects with an advanced stage at diagnosis, poorly-differentiated tumours, or increased levels of ascites as compared to subjects with an early stage, well-differentiated tumour(s), and less ascites. Tumour-derived VEGF may play a role in ascites formation. Angiogenesis has been shown to be a negative predictive factor for overall survival and disease-free survival in women with advanced ovarian cancer 18. Blockade or inhibition of VEGF (eg, using bevacizumab) or VEGFR (using TKIs) have been shown to be effective in Phase II studies in ovarian cancer. For example, single-agent bevacizumab has shown a 16-21% overall tumour response rate (ORR) in two studies of previously treated patients with ovarian cancer.Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, -3, PDGFR-α and -β and c-Kit. Pazopanib has shown evidence of antitumor activity in clinical studies of ovarian cancer. VEG104450 is a Phase II study of pazopanib in subjects with ovarian, fallopian tube, or primary peritoneal cancers who had responded to first-line chemotherapy and who were at high risk of clinical recurrence (as evidenced by rising CA-125 levels). 36 subjects were enrolled, of which 22 (61%) had a sensitive platinum relapse and a previous chemotherapy regimen. Final results obtained recently indicate the following:10 out of 36 (28%) subjects experienced a CA-125 response to pazopanib with responses occurring shortly after start of pazopanib administration (median time to response 29 days) with a median duration of response of 113 days 21.Taking into account theses results, pazopanib is one of the promising antiangiogenic therapies to be studied against ovarian cancer