Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

K. Kalinsky, Joseph A. Sparano, X. Zhong, E. Andreopoulou, B. Taback, L. Wiechmann, Sheldon M. Feldman, P. Ananthakrishnan, A. Ahmad, S. Cremers, A. N. Sireci, J. R. Cross, D. K. Marks, P. Mundi, E. Connolly, K. D. Crew, M. A. Maurer, H. Hibshoosh, S. Lee, D. L. Hershman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Introduction: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC. Materials and methods: Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. Results: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). Conclusion: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalClinical and Translational Oncology
DOIs
StateAccepted/In press - May 7 2018

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Breast Neoplasms
Neoplasms
Phosphatidylinositol 3-Kinases
Pharmacokinetics
Stathmin
Insulin
Insulin-Like Growth Factor Binding Protein 3
Mucositis
MK 2206
C-Peptide
Pruritus
Tumor Biomarkers
Genomics
Exanthema
Drug-Related Side Effects and Adverse Reactions
Population
Intercellular Signaling Peptides and Proteins
Biomarkers
Biopsy
Glucose

Keywords

  • AKT inhibitor
  • Breast cancer
  • MK-2206
  • Phase 0
  • Pre-surgical

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer : a New York Cancer Consortium trial. / Kalinsky, K.; Sparano, Joseph A.; Zhong, X.; Andreopoulou, E.; Taback, B.; Wiechmann, L.; Feldman, Sheldon M.; Ananthakrishnan, P.; Ahmad, A.; Cremers, S.; Sireci, A. N.; Cross, J. R.; Marks, D. K.; Mundi, P.; Connolly, E.; Crew, K. D.; Maurer, M. A.; Hibshoosh, H.; Lee, S.; Hershman, D. L.

In: Clinical and Translational Oncology, 07.05.2018, p. 1-10.

Research output: Contribution to journalArticle

Kalinsky, K, Sparano, JA, Zhong, X, Andreopoulou, E, Taback, B, Wiechmann, L, Feldman, SM, Ananthakrishnan, P, Ahmad, A, Cremers, S, Sireci, AN, Cross, JR, Marks, DK, Mundi, P, Connolly, E, Crew, KD, Maurer, MA, Hibshoosh, H, Lee, S & Hershman, DL 2018, 'Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial', Clinical and Translational Oncology, pp. 1-10. https://doi.org/10.1007/s12094-018-1888-2
Kalinsky, K. ; Sparano, Joseph A. ; Zhong, X. ; Andreopoulou, E. ; Taback, B. ; Wiechmann, L. ; Feldman, Sheldon M. ; Ananthakrishnan, P. ; Ahmad, A. ; Cremers, S. ; Sireci, A. N. ; Cross, J. R. ; Marks, D. K. ; Mundi, P. ; Connolly, E. ; Crew, K. D. ; Maurer, M. A. ; Hibshoosh, H. ; Lee, S. ; Hershman, D. L. / Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer : a New York Cancer Consortium trial. In: Clinical and Translational Oncology. 2018 ; pp. 1-10.
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abstract = "Introduction: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC. Materials and methods: Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. Results: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). Conclusion: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.",
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T1 - Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer

T2 - a New York Cancer Consortium trial

AU - Kalinsky, K.

AU - Sparano, Joseph A.

AU - Zhong, X.

AU - Andreopoulou, E.

AU - Taback, B.

AU - Wiechmann, L.

AU - Feldman, Sheldon M.

AU - Ananthakrishnan, P.

AU - Ahmad, A.

AU - Cremers, S.

AU - Sireci, A. N.

AU - Cross, J. R.

AU - Marks, D. K.

AU - Mundi, P.

AU - Connolly, E.

AU - Crew, K. D.

AU - Maurer, M. A.

AU - Hibshoosh, H.

AU - Lee, S.

AU - Hershman, D. L.

PY - 2018/5/7

Y1 - 2018/5/7

N2 - Introduction: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC. Materials and methods: Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. Results: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). Conclusion: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

AB - Introduction: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC. Materials and methods: Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. Results: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). Conclusion: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

KW - AKT inhibitor

KW - Breast cancer

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KW - Phase 0

KW - Pre-surgical

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