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.
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.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: Julia Willner; Kaitlyn Wurz; Kimberly H Allison; Vijaya Galic; Rochelle L Garcia; Barbara A Goff; Elizabeth M Swisher Journal: Hum Pathol Date: 2007-01-29 Impact factor: 3.466
Authors: C F Verschraegen; T Sittisomwong; A P Kudelka; E d Guedes; M Steger; T Nelson-Taylor; M Vincent; R Rogers; E N Atkinson; J J Kavanagh Journal: J Clin Oncol Date: 2000-07 Impact factor: 44.544
Authors: Roman K Thomas; Alissa C Baker; Ralph M Debiasi; Wendy Winckler; Thomas Laframboise; William M Lin; Meng Wang; Whei Feng; Thomas Zander; Laura MacConaill; Laura E Macconnaill; Jeffrey C Lee; Rick Nicoletti; Charlie Hatton; Mary Goyette; Luc Girard; Kuntal Majmudar; Liuda Ziaugra; Kwok-Kin Wong; Stacey Gabriel; Rameen Beroukhim; Michael Peyton; Jordi Barretina; Amit Dutt; Caroline Emery; Heidi Greulich; Kinjal Shah; Hidefumi Sasaki; Adi Gazdar; John Minna; Scott A Armstrong; Ingo K Mellinghoff; F Stephen Hodi; Glenn Dranoff; Paul S Mischel; Tim F Cloughesy; Stan F Nelson; Linda M Liau; Kirsten Mertz; Mark A Rubin; Holger Moch; Massimo Loda; William Catalona; Jonathan Fletcher; Sabina Signoretti; Frederic Kaye; Kenneth C Anderson; George D Demetri; Reinhard Dummer; Stephan Wagner; Meenhard Herlyn; William R Sellers; Matthew Meyerson; Levi A Garraway Journal: Nat Genet Date: 2007-02-11 Impact factor: 38.330
Authors: Katherine Stemke-Hale; Ana Maria Gonzalez-Angulo; Ana Lluch; Richard M Neve; Wen-Lin Kuo; Michael Davies; Mark Carey; Zhi Hu; Yinghui Guan; Aysegul Sahin; W Fraser Symmans; Lajos Pusztai; Laura K Nolden; Hugo Horlings; Katrien Berns; Mien-Chie Hung; Marc J van de Vijver; Vicente Valero; Joe W Gray; René Bernards; Gordon B Mills; Bryan T Hennessy Journal: Cancer Res Date: 2008-08-01 Impact factor: 12.701
Authors: Natasha B Leighl; Susan Dent; Mark Clemons; Theodore A Vandenberg; Richard Tozer; David G Warr; R Michael Crump; David Hedley; Gregory R Pond; Janet E Dancey; Malcolm J Moore Journal: Breast Cancer Res Treat Date: 2007-04-26 Impact factor: 4.872
Authors: Bryan T Hennessy; Yiling Lu; Enrique Poradosu; Qianghua Yu; Shuangxing Yu; Hassan Hall; Mark S Carey; Murali Ravoori; Ana Maria Gonzalez-Angulo; Robert Birch; I Craig Henderson; Vikas Kundra; Gordon B Mills Journal: Clin Cancer Res Date: 2007-12-15 Impact factor: 12.531
Authors: Anil Kumar; Thurl E Harris; Susanna R Keller; Kin M Choi; Mark A Magnuson; John C Lawrence Journal: Mol Cell Biol Date: 2007-10-29 Impact factor: 4.272
Authors: Hanxiao Wang; Stefanie Galbán; Rong Wu; Brittany M Bowman; Amanda Witte; Katrin Vetter; Craig J Galbán; Brian D Ross; Kathleen R Cho; Alnawaz Rehemtulla Journal: Clin Cancer Res Date: 2012-10-24 Impact factor: 12.531
Authors: Ivana Gojo; Alexander Perl; Selina Luger; Maria R Baer; Kelly J Norsworthy; Kenneth S Bauer; Michael Tidwell; Stephanie Fleckinger; Martin Carroll; Edward A Sausville Journal: Invest New Drugs Date: 2013-02-27 Impact factor: 3.850