Paclitaxel/Pazopanib for Platinum Resistant/Refractory Ovarian Cancer
Condition: Ovarian Cancer
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
Study type: Interventional
Phase: Phase 2

Summary: 
      Study of Pazopanib and weekly Paclitaxel in patients with platinum resistant/refractory
      ovarian cancer who relapse during bevacizumab maintenance.
    

Detailed description: 
      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
    

Intervention name(s): Pazopanib; Paclitaxel
Intervention type(s): Drug; Drug
Intervention description(s): Pazopanib 600mg during the fist cycle. Then, if there is not heptic triuyble, the dose could be increased to 800mg; Arm 1 : Paclitaxel 65mg/m² Arm 2: Paclitaxel 80mg/m²
Other intervention name(s): Votrient; Taxol
Intervention MeSH terms: Paclitaxel
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment