Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer

ObjectivesOn the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer.MethodsPatients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n = 10; taxane refractory, n = 11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and 18F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies.ResultsPatients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with a PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with 18F-FDG-PET responses.ConclusionsPatients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m2 every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.

► Patients with an aberrant PI3K/AKT pathway responded to combined therapy using an AKT inhibitor, perifosine, plus docetaxel.
► Patients with KRAS mutations showed rapid progression.
► Decreased phosphorylated S6 correlated with 18F-FDG-PET responses.
► Protective pathways such as ERK were enhanced after AKT inhibition by perifosine.