A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer

Cynthia X. Ma, Cesar Sanchez, Feng Gao, Robert Crowder, Michael Naughton, Timothy Pluard, Allison Creekmore, Zhanfang Guo, Jeremy Hoog, Albert Lockhart, Austin Doyle, Charles Erlichman, Matthew J. Ellis

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor-positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER+HER2- breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/ fulvestrant. Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%-63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+ HER2- breast cancer.

Original languageEnglish (US)
Pages (from-to)2650-2658
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number11
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

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Estrogen Receptors
Breast Neoplasms
Estrogens
Therapeutics
Maximum Tolerated Dose
Apoptosis
MK 2206
Cell Line
Prednisone
fulvestrant
Exanthema
Phosphatidylinositol 3-Kinases
Research Design
anastrozole
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer. / Ma, Cynthia X.; Sanchez, Cesar; Gao, Feng; Crowder, Robert; Naughton, Michael; Pluard, Timothy; Creekmore, Allison; Guo, Zhanfang; Hoog, Jeremy; Lockhart, Albert; Doyle, Austin; Erlichman, Charles; Ellis, Matthew J.

In: Clinical Cancer Research, Vol. 22, No. 11, 01.06.2016, p. 2650-2658.

Research output: Contribution to journalArticle

Ma, CX, Sanchez, C, Gao, F, Crowder, R, Naughton, M, Pluard, T, Creekmore, A, Guo, Z, Hoog, J, Lockhart, A, Doyle, A, Erlichman, C & Ellis, MJ 2016, 'A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer', Clinical Cancer Research, vol. 22, no. 11, pp. 2650-2658. https://doi.org/10.1158/1078-0432.CCR-15-2160
Ma, Cynthia X. ; Sanchez, Cesar ; Gao, Feng ; Crowder, Robert ; Naughton, Michael ; Pluard, Timothy ; Creekmore, Allison ; Guo, Zhanfang ; Hoog, Jeremy ; Lockhart, Albert ; Doyle, Austin ; Erlichman, Charles ; Ellis, Matthew J. / A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 11. pp. 2650-2658.
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abstract = "Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor-positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER+HER2- breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/ fulvestrant. Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42{\%} (95{\%} CI, 23{\%}-63{\%}) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+ HER2- breast cancer.",
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T1 - A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer

AU - Ma, Cynthia X.

AU - Sanchez, Cesar

AU - Gao, Feng

AU - Crowder, Robert

AU - Naughton, Michael

AU - Pluard, Timothy

AU - Creekmore, Allison

AU - Guo, Zhanfang

AU - Hoog, Jeremy

AU - Lockhart, Albert

AU - Doyle, Austin

AU - Erlichman, Charles

AU - Ellis, Matthew J.

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N2 - Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor-positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER+HER2- breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/ fulvestrant. Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%-63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+ HER2- breast cancer.

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