Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study

Shannon N. Westin, Michael W. Sill, Robert L. Coleman, Steven Waggoner, Kathleen N. Moore, Cara A. Mathews, Lainie P. Martin, Susan C. Modesitt, Sanghoon Lee, Zhenlin Ju, Gordon B. Mills, Russell J. Schilder, Paula M. Fracasso, Michael J. Birrer, Carol Aghajanian

    Research output: Contribution to journalArticle

    Abstract

    Objective: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. Methods: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). Results: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0–15%) and 1 response in DL-1 (8.3%, 90%CI 0.4–33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. Conclusion: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.

    Original languageEnglish (US)
    JournalGynecologic oncology
    DOIs
    StateAccepted/In press - Jan 1 2019

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    Mitogen-Activated Protein Kinase Kinases
    Endometrial Neoplasms
    Safety
    Mucositis
    Exanthema
    Phosphatidylinositol 3-Kinases
    Dehydration
    Acute Kidney Injury
    Histology
    Stroke
    Hypertension
    Mutation
    trametinib
    GSK2141795

    Keywords

    • AKT inhibition
    • Endometrial cancer
    • KRAS mutation
    • MEK inhibition
    • NRG oncology
    • PI3K

    ASJC Scopus subject areas

    • Oncology
    • Obstetrics and Gynecology

    Cite this

    Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer : An NRG Oncology/GOG study. / Westin, Shannon N.; Sill, Michael W.; Coleman, Robert L.; Waggoner, Steven; Moore, Kathleen N.; Mathews, Cara A.; Martin, Lainie P.; Modesitt, Susan C.; Lee, Sanghoon; Ju, Zhenlin; Mills, Gordon B.; Schilder, Russell J.; Fracasso, Paula M.; Birrer, Michael J.; Aghajanian, Carol.

    In: Gynecologic oncology, 01.01.2019.

    Research output: Contribution to journalArticle

    Westin, SN, Sill, MW, Coleman, RL, Waggoner, S, Moore, KN, Mathews, CA, Martin, LP, Modesitt, SC, Lee, S, Ju, Z, Mills, GB, Schilder, RJ, Fracasso, PM, Birrer, MJ & Aghajanian, C 2019, 'Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study', Gynecologic oncology. https://doi.org/10.1016/j.ygyno.2019.09.024
    Westin, Shannon N. ; Sill, Michael W. ; Coleman, Robert L. ; Waggoner, Steven ; Moore, Kathleen N. ; Mathews, Cara A. ; Martin, Lainie P. ; Modesitt, Susan C. ; Lee, Sanghoon ; Ju, Zhenlin ; Mills, Gordon B. ; Schilder, Russell J. ; Fracasso, Paula M. ; Birrer, Michael J. ; Aghajanian, Carol. / Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer : An NRG Oncology/GOG study. In: Gynecologic oncology. 2019.
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    abstract = "Objective: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. Methods: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). Results: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58{\%}) and serous (27{\%}). Four of 25 (16{\%}) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0{\%}, 90{\%}CI 0–15{\%}) and 1 response in DL-1 (8.3{\%}, 90{\%}CI 0.4–33.9{\%}). Proportion PFS at 6 months for DL1 is 14{\%}, and 25{\%} for DL-1. Conclusion: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.",
    keywords = "AKT inhibition, Endometrial cancer, KRAS mutation, MEK inhibition, NRG oncology, PI3K",
    author = "Westin, {Shannon N.} and Sill, {Michael W.} and Coleman, {Robert L.} and Steven Waggoner and Moore, {Kathleen N.} and Mathews, {Cara A.} and Martin, {Lainie P.} and Modesitt, {Susan C.} and Sanghoon Lee and Zhenlin Ju and Mills, {Gordon B.} and Schilder, {Russell J.} and Fracasso, {Paula M.} and Birrer, {Michael J.} and Carol Aghajanian",
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    TY - JOUR

    T1 - Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer

    T2 - An NRG Oncology/GOG study

    AU - Westin, Shannon N.

    AU - Sill, Michael W.

    AU - Coleman, Robert L.

    AU - Waggoner, Steven

    AU - Moore, Kathleen N.

    AU - Mathews, Cara A.

    AU - Martin, Lainie P.

    AU - Modesitt, Susan C.

    AU - Lee, Sanghoon

    AU - Ju, Zhenlin

    AU - Mills, Gordon B.

    AU - Schilder, Russell J.

    AU - Fracasso, Paula M.

    AU - Birrer, Michael J.

    AU - Aghajanian, Carol

    PY - 2019/1/1

    Y1 - 2019/1/1

    N2 - Objective: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. Methods: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). Results: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0–15%) and 1 response in DL-1 (8.3%, 90%CI 0.4–33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. Conclusion: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.

    AB - Objective: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. Methods: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). Results: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0–15%) and 1 response in DL-1 (8.3%, 90%CI 0.4–33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. Conclusion: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.

    KW - AKT inhibition

    KW - Endometrial cancer

    KW - KRAS mutation

    KW - MEK inhibition

    KW - NRG oncology

    KW - PI3K

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    U2 - 10.1016/j.ygyno.2019.09.024

    DO - 10.1016/j.ygyno.2019.09.024

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    JO - Gynecologic Oncology

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