-  After surgery, most of patients with advanced ovarian/primitive peritoneal /fallopian
           carcinoma received as first line treatment, carboplatin plus paclitaxel plus or minus
           bevacizumab for 6 cycles followed by surveillance or bevacizumab maintenance therapy up
           to one year (GOG (Burger et al.), ICON7 (Perren et al.), French national guidelines
           Saint Paul de Vence (www.arcagy.org)).

        -  This multi-modality approach achieves clinical responses in about 70% of patients,
           although a majority of women eventually relapse and die from disease progression. The
           first sign of relapse can be a progressively rising CA-125 (Tuxen et al.).

        -  Biochemical-recurrent of Epithelial Ovarian Cancer (EOC) is defined as CA-125 elevation
           above normal values without clinical evidence of disease, and can predate clinical
           disease by approximately 3-6 months (Tuxen et al.). Even if CA-125 elevation is a
           harbinger of EOC relapse, the question remains as to whether early therapeutic
           intervention can translate into extending the duration of survival.

        -  A few years ago, Rustin reported from ovarian cancer patients on surveillance after
           first line treatment with isolated elevated CA-125 (without RECIST/symptoms criteria)
           that there was no benefit to initiate a new chemotherapy compared to surveillance
           (Rustin et al. Lancet 2010; Rustin et al. Ann Oncol 2011).

        -  For patients under bevacizumab on maintenance phase at the time of the CA-125 elevation
           without RECIST or symptoms progression, data are scare. In the GOG0218 trial, elevated
           CA-125 did not totally complied with RECIST criteria progression. This study reported
           that the median PFS is longer in patients with continuous bevacizumab (14.1 months),
           compared to patients under placebo (10.3 months), using CA-125 & RECIST criteria,
           supporting the hypothesis that a maintenance treatment with an anti angiogenic agent
           allows delaying disease progression (Burger et al. N. Engl. J. Med. 2011). In an
           analysis of progression-free survival in which data for patients with increased CA-125
           levels were censored, the median progression-free survival was 12.0 months in the
           control group but 18.0 months in the bevacizumab-throughout group (hazard ratio, 0.645;
           P<0.001). The relationship of CA-125 to progressive disease (PD) may be altered in
           bevacizumab (BV)-treated patients. In the Ocean trial elevated CA-125 was associated
           with forthcoming progression for the majority of the patients under bevacizumab (HR
           0.48) in the platinum sensitive population (Aghajanian et al.).

        -  Current international recommendations are to continue the same strategy (surveillance or
           maintenance bevacizumab) until RECIST or symptomatic progression regardless of the
           CA-125 level.

        -  However, some can argue that a waiting attitude is deemed unacceptable due to patient
           anxiety over a rising CA-125 compelling a significant proportion of physicians to
           propose a therapeutic intervention, due to the nearness of the disease progression.

        -  Tamoxifen is an endocrine alternative treatment option in patients with rising CA-125.
           Hurteau et al. studies supported the use of tamoxifen showing a 17% response rate in
           measurable recurrent disease, 13% response rate in platinum resistant disease, observed
           stable disease in 38% of patients lasting a median of 3 months (Hatch, et al).

        -  The use of tamoxifen treatment as a control arm for isolated CA-125 is thus justified
           based on a favorable toxicity profile compared with available cytotoxic agents and the
           lack of interference with subsequent interventions beyond documentation of clinical
           progression (Marckman, et al). As patients have until today no benefit to introduce a
           new chemotherapy regimen for isolated elevated CA-125 (Rustin et al 2010), exploring new
           anti-angiogenic agent could be clinically relevant. Agents that inhibit tumor
           angiogenesis and invasion were considered to be ideal candidates for the experimental
           arm given their potential to prolong the duration of disease-free survival while
           exhibiting a more favorable toxicity profile than cytotoxic drugs.

        -  Pazopanib and other multi-kinase inhibitors such as cediranib, nintenanib reported
           activity in relapsing ovarian cancer (sensitive or resistant population) used alone in
           several phase II trials (Matulonis et al., Ledermann et al., and Friedlander et al.).

        -  Regorafenib is a new oral multi-kinase inhibitor. It inhibits kinases involved in
           angiogenesis (VEGFR 1-3, TIE 2), signaling in the tumor microenvironment (PDGFR-β, FGFR)
           and oncogenesis (KIT, RET and BRAF). Inhibition of tumor growth and formation of
           metastases were shown in vivo. Tumor activity has been reported in a variety of tumor
           types. Regorafenib is approved in Europe for the treatment of metastatic colorectal
           cancer in patients previously treated with, or who are not considered candidates for,
           available therapies. An application for GIST progressing after imatinib and sunitinib
           has obtained the AMM in Europe. The recommended dose is 160 mg taken once daily for 3
           weeks followed by 1 week off therapy.

      The objective of this randomized phase II is to evaluate the benefit of regorafenib for
      ovarian patients who reported a confirmed elevated CA-125 level under surveillance or
      bevacizumab, compared with tamoxifen.