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

Siqing Fu, Bryan T. Hennessy, Chaan S. Ng, Zhenlin Ju, Kevin R. Coombes, Judith K. Wolf, Anil K. Sood, Charles F. Levenback, Robert L. Coleman, John J. Kavanagh, David M. Gershenson, Maurie Markman, Kristine Dice, Adrienne Howard, Jane Li, Yang Li, Katherine Stemke-Hale, Mary Dyer, Edward Atkinson, Ed JacksonVikas Kundra, Razelle Kurzrock, Robert C. Bast, Gordon Mills

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 18F-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 18F-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.

Original languageEnglish (US)
Pages (from-to)47-53
Number of pages7
JournalGynecologic Oncology
Volume126
Issue number1
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

Fingerprint

docetaxel
Platinum
Fluorodeoxyglucose F18
Phosphatidylinositol 3-Kinases
Mutation
S 6
Ovarian epithelial cancer
taxane
perifosine
Ovarian Neoplasms
Disease-Free Survival

Keywords

  • AKT
  • Docetaxel
  • Epithelial ovarian cancer
  • Perfosine
  • Platinum resistance
  • Taxane resistance

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

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

In: Gynecologic Oncology, Vol. 126, No. 1, 01.07.2012, p. 47-53.

Research output: Contribution to journalArticle

Fu, S, Hennessy, BT, Ng, CS, Ju, Z, Coombes, KR, Wolf, JK, Sood, AK, Levenback, CF, Coleman, RL, Kavanagh, JJ, Gershenson, DM, Markman, M, Dice, K, Howard, A, Li, J, Li, Y, Stemke-Hale, K, Dyer, M, Atkinson, E, Jackson, E, Kundra, V, Kurzrock, R, Bast, RC & Mills, G 2012, 'Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer', Gynecologic Oncology, vol. 126, no. 1, pp. 47-53. https://doi.org/10.1016/j.ygyno.2012.04.006
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. / Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer. In: Gynecologic Oncology. 2012 ; Vol. 126, No. 1. pp. 47-53.
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T1 - Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer

AU - Fu, Siqing

AU - Hennessy, Bryan T.

AU - Ng, Chaan S.

AU - Ju, Zhenlin

AU - Coombes, Kevin R.

AU - Wolf, Judith K.

AU - Sood, Anil K.

AU - Levenback, Charles F.

AU - Coleman, Robert L.

AU - Kavanagh, John J.

AU - Gershenson, David M.

AU - Markman, Maurie

AU - Dice, Kristine

AU - Howard, Adrienne

AU - Li, Jane

AU - Li, Yang

AU - Stemke-Hale, Katherine

AU - Dyer, Mary

AU - Atkinson, Edward

AU - Jackson, Ed

AU - Kundra, Vikas

AU - Kurzrock, Razelle

AU - Bast, Robert C.

AU - Mills, Gordon

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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 18F-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 18F-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.

AB - 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 18F-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 18F-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.

KW - AKT

KW - Docetaxel

KW - Epithelial ovarian cancer

KW - Perfosine

KW - Platinum resistance

KW - Taxane resistance

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