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

• Published in: Gynecologic oncology 2012-07, Vol.126 (1), p.47-53
• Main Authors: Fu, Siqing, Hennessy, Bryan T, Ng, Chaan S, Ju, Zhenlin, Coombes, Kevin R, Wolf, Judith K, Sood, Anil K, Levenback, Charles F, Coleman, Robert L, Kavanagh, John J, Gershenson, David M, Markman, Maurie, Dice, Kristine, Howard, Adrienne, Li, Jane, Li, Yang, Stemke-Hale, Katherine, Dyer, Mary, Atkinson, Edward, Jackson, Ed, Kundra, Vikas, Kurzrock, Razelle, Bast, Robert C, Mills, Gordon B
• Format: Article
• Language: English
• Subjects: Aged; AKT; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Epithelial ovarian cancer; Female; Fluorodeoxyglucose F18; Hematology, Oncology and Palliative Medicine; Humans; Middle Aged; Neoplasm Grading; Neoplasms, Glandular and Epithelial - blood; Neoplasms, Glandular and Epithelial - diagnostic imaging; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - pathology; Obstetrics and Gynecology; Organoplatinum Compounds - pharmacology; Ovarian Neoplasms - blood; Ovarian Neoplasms - diagnostic imaging; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Perfosine; Phosphorylcholine - administration & dosage; Phosphorylcholine - analogs & derivatives; Platinum resistance; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Taxane resistance; Taxoids - administration & dosage; Taxoids - pharmacology
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2012.04.006

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 and18 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 with18 F-FDG-PET responses. Conclusions Patients 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.