The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study

Peter Tan, Ing Soo Tiong, Shaun Fleming, Giovanna Pomilio, Nik Cummings, Mark Droogleever, Julie McManus, Anthony Schwarer, John Catalano, Sushrut Patil, Sharon Avery, Andrew Spencer, Andrew Wei

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5–21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1–5 and 8–9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.
Original languageEnglish
Pages (from-to)52269-52280
Number of pages12
JournalOncotarget
Volume8
Issue number32
DOIs
Publication statusPublished - 2017

Cite this

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title = "The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study",
abstract = "Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5–21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1–5 and 8–9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73{\%}), thrombocytopenia (67{\%}), mucositis (24{\%}) and febrile neutropenia (19{\%}). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5{\%}. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50{\%} vs. 16{\%}, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.",
author = "Peter Tan and Tiong, {Ing Soo} and Shaun Fleming and Giovanna Pomilio and Nik Cummings and Mark Droogleever and Julie McManus and Anthony Schwarer and John Catalano and Sushrut Patil and Sharon Avery and Andrew Spencer and Andrew Wei",
year = "2017",
doi = "10.18632/oncotarget.13699",
language = "English",
volume = "8",
pages = "52269--52280",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
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The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia : a phase Ib/II study. / Tan, Peter; Tiong, Ing Soo; Fleming, Shaun; Pomilio, Giovanna; Cummings, Nik; Droogleever, Mark; McManus, Julie; Schwarer, Anthony; Catalano, John; Patil, Sushrut; Avery, Sharon; Spencer, Andrew; Wei, Andrew.

In: Oncotarget, Vol. 8, No. 32, 2017, p. 52269-52280.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia

T2 - a phase Ib/II study

AU - Tan, Peter

AU - Tiong, Ing Soo

AU - Fleming, Shaun

AU - Pomilio, Giovanna

AU - Cummings, Nik

AU - Droogleever, Mark

AU - McManus, Julie

AU - Schwarer, Anthony

AU - Catalano, John

AU - Patil, Sushrut

AU - Avery, Sharon

AU - Spencer, Andrew

AU - Wei, Andrew

PY - 2017

Y1 - 2017

N2 - Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5–21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1–5 and 8–9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.

AB - Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5–21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1–5 and 8–9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.

U2 - 10.18632/oncotarget.13699

DO - 10.18632/oncotarget.13699

M3 - Article

VL - 8

SP - 52269

EP - 52280

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 32

ER -