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

Abstract

Objectives: On 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.

Methods: Patients 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 (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies.

Results: Patients 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 (18)F-FDG-PET responses.

Conclusions: Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m(2) 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.

Figure 1

The waterfall plot displays best tumor responses by RECIST 1.0 criteria. All 21 patients were evaluated. Patients represented by black bars either have new lesions or early progression, or early withdrawal for other reasons. They are arbitrarily designated as having a 21% progression. Duration of response and stable disease are indicated.

Figure 2

Protein expression profiles of tumor tissues at baseline and after treatment with perifosine for 7 days were analyzed by reverse-phase protein arrays (RPPA). Figure 2A indicates unsupervised hierarchical clustering analysis using all proteins. Figure 2B displays unsupervised hierarchical clustering analysis using proteins identified by a paired t-test analysis. Figure 2C shows unsupervised hierarchical clustering analysis using proteins identified by two-group t-test analysis.

Figure 2

Protein expression profiles of tumor tissues at baseline and after treatment with perifosine for 7 days were analyzed by reverse-phase protein arrays (RPPA). Figure 2A indicates unsupervised hierarchical clustering analysis using all proteins. Figure 2B displays unsupervised hierarchical clustering analysis using proteins identified by a paired t-test analysis. Figure 2C shows unsupervised hierarchical clustering analysis using proteins identified by two-group t-test analysis.

Figure 2

Protein expression profiles of tumor tissues at baseline and after treatment with perifosine for 7 days were analyzed by reverse-phase protein arrays (RPPA). Figure 2A indicates unsupervised hierarchical clustering analysis using all proteins. Figure 2B displays unsupervised hierarchical clustering analysis using proteins identified by a paired t-test analysis. Figure 2C shows unsupervised hierarchical clustering analysis using proteins identified by two-group t-test analysis.