Standard of treatments:~In Europe, advanced ovarian cancer patients are treated in first line with optimal debulking surgery followed by carboplatin/paclitaxel regimen plus bevacizumab during chemotherapy and as maintenance for a total à 15 months. The addition of bevacizumab is a standard for the patients with residual disease.~The addition of bevacizumab to carboplatin/gemcitabine chemotherapy was also recently approved for patients with platinum sensible relapse [Aghajanian, 2012]. The bevacizumab is maintained until progression.~Rationale to use anti-angiogenic agents in early relapse:~The recent AURELIA trial comparing paclitaxel, topotecan or liposomal doxorubicin alone versus combined to bevacizumab after early failure of the first-line with carboplatin/paclitaxel revealed that targeting angiogenesis was beneficial in recurrent platinum-resistant ovarian cancer [Pujade-Lauraine, 2012 and 2013], with higher progression-free survival (PFS). Thus, the strategy of inhibiting angiogenesis in recurrent resistant-platinum ovarian cancer is very promising.~The recent changes of the standard of treatment of first line and platinum-sensible relapse of patients with ovarian cancer highlights the question of inhibiting angiogenesis for relapse during/after bevacizumab maintenance. In this last situation, the strategy of continuation of antiangiogenesis therapy, just in changing chemotherapy despite recurrence, showed benefit in other types of cancer (colon, lung). In ovarian cancer, no study has been performed to answer to the question. In Aurelia trial, However, patients did not previously receive bevacizumab.~The choice of the best antiangiogenic agent in alternative to bevacizumab needs to be assessed. Small molecular inhibitor of tyrosine-protein-kinases (TK) could be used with efficacy after a first-line of antiangiogenesis treatment as it was demonstrated in renal cancer [Escudier, 2011].~Pazopanib is an oral, potent multi-targeted small-molecule inhibitor of VEGF-receptor TKs (VEGFR-1 -2 -3 PDGFR and c-KIT; it is the first targeted small molecule that it has demonstrated an important activity in ovarian cancer. At ASCO 2013, the AGO-OVAR16 trial of maintenance of pazopanib in first line ovarian cancer has shown a benefit in progression free survival (difference of 5.6 months of median PFS in favour of pazopanib compared to placebo) [Dubois, ASCO 2013 LBA5503]; in this trial, the majority of the patients had few residual disease and patients did not receive bevacizumab.~In ovarian cancer, the standard treatment for patients relapsing during bevacizumab maintenance (15 to 20% of patients) is still a mono-chemotherapy. Weekly paclitaxel is one oh the most commonly used chemotherapy in this situation of early relapse. However, the promising results of pazopanib in first line led to develop protocols in second-line in combination with chemotherapy.~The combination of weekly paclitaxel and pazopanib is feasible and the dose proposed for further phase 2 studies is pazopanib 800 mg daily and paclitaxel 65 mg/m2 at day 1, 8, 15 every 28 days [Tan, the oncologist 2010]. The dosage of paclitaxel was justified on results from previous studies, demonstrating that co-administration of pazopanib and paclitaxel increases the systemic exposure to paclitaxel. An Italian group has just closed a phase 2 study (MITO11) that evaluated this association among ovarian patients with early relapse. In this study, patients did not receive previously bevacizumab.~Thus, pazopanib is the best molecule to be associated to chemotherapy in ovarian cancer patients who early relapse after a treatment including bevacizumab.~We propose a randomized phase 2 trial to evaluate the combination of pazopanib to weekly paclitaxel among patients with platine resistant relapse after treatment including bevacizumab maintenance
Study of Pazopanib and weekly Paclitaxel in patients with platinum resistant/refractory ovarian cancer who relapse during bevacizumab maintenance.