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 Jackson; Vikas Kundra; Razelle Kurzrock; Robert C. Bast; Gordon B. Mills

doi:10.1016/j.ygyno.2012.04.006

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 B. Mills

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

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 language	English (US)
Pages (from-to)	47-53
Number of pages	7
Journal	Gynecologic oncology
Volume	126
Issue number	1
DOIs	https://doi.org/10.1016/j.ygyno.2012.04.006
State	Published - Jul 2012
Externally published	Yes

Keywords

AKT
Docetaxel
Epithelial ovarian cancer
Perfosine
Platinum resistance
Taxane resistance

ASJC Scopus subject areas

Oncology
Obstetrics and Gynecology

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10.1016/j.ygyno.2012.04.006

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Fu, S., Hennessy, B. T., Ng, C. S., Ju, Z., Coombes, K. R., Wolf, J. K., Sood, A. K., Levenback, C. F., Coleman, R. L., Kavanagh, J. J., Gershenson, D. M., Markman, M., Dice, K., Howard, A., Li, J., Li, Y., Stemke-Hale, K., Dyer, M., Atkinson, E., ... Mills, G. B. (2012). Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer. Gynecologic oncology, 126(1), 47-53. https://doi.org/10.1016/j.ygyno.2012.04.006

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, GB 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

@article{426dc797aabf485aa1ac6ceda1339daa,

title = "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 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.",

keywords = "AKT, Docetaxel, Epithelial ovarian cancer, Perfosine, Platinum resistance, Taxane resistance",

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

note = "Funding Information: The authors thank Joann Aaron in the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center for editing our manuscript, and financial support in part from The Commonwealth Foundation for Cancer Research (SF), Keryx Biopharmaceuticals (SF), MD Anderson Cancer Clinical Research Fund (SF), UT MD Anderson Ovarian Cancer SPORE philanthropic fund (RB), UT MD Anderson Ovarian Cancer SPORE ( NIH P50CA83639 to RB and GBM), SUC2-AACR-DT0209 01 (GBM), an American Society of Clinical Oncology (ASCO) Cancer Foundation Career Development Award (CDA to BTH), a Science Foundation Ireland (SFI)/Health Research Board (HRB Ireland) Translational Research Award (TRA to BTH) for the clinical and correlative studies and National Cancer Institute through The University of Texas MD Anderson Cancer Center Support Grant ( P30 CA016672 ).",

year = "2012",

month = jul,

doi = "10.1016/j.ygyno.2012.04.006",

language = "English (US)",

volume = "126",

pages = "47--53",

journal = "Gynecologic oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

number = "1",

}

TY - JOUR

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 B.

N1 - Funding Information: The authors thank Joann Aaron in the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center for editing our manuscript, and financial support in part from The Commonwealth Foundation for Cancer Research (SF), Keryx Biopharmaceuticals (SF), MD Anderson Cancer Clinical Research Fund (SF), UT MD Anderson Ovarian Cancer SPORE philanthropic fund (RB), UT MD Anderson Ovarian Cancer SPORE ( NIH P50CA83639 to RB and GBM), SUC2-AACR-DT0209 01 (GBM), an American Society of Clinical Oncology (ASCO) Cancer Foundation Career Development Award (CDA to BTH), a Science Foundation Ireland (SFI)/Health Research Board (HRB Ireland) Translational Research Award (TRA to BTH) for the clinical and correlative studies and National Cancer Institute through The University of Texas MD Anderson Cancer Center Support Grant ( P30 CA016672 ).

PY - 2012/7

Y1 - 2012/7

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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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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