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

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

doi:10.18632/oncotarget.13699

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.

Highlights

Mammalian target of rapamycin is a serine/threonine protein kinase regulating cell growth, proliferation, survival, autophagy, gene transcription and protein synthesis
We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin inhibitor, everolimus in combination with azacitidine 75 mg/m2 subcutaneously in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2)
This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced acute myeloid leukemia (AML)

Summary

INTRODUCTION

Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase regulating cell growth, proliferation, survival, autophagy, gene transcription and protein synthesis. Small molecule targeting of mTOR has been shown to selectively inhibit the clonogenic function of leukemic, www.impactjournals.com/oncotarget but not normal progenitors, suggesting a potential role in modulating relapse from surviving progenitors after conventional cytotoxic approaches [8,9,10]. MTOR inhibitors have limited clinical activity in AML as monotherapy [8, 11,12,13,14], combination with cytotoxic approaches appears more promising. Only one clinical study has combined an mTOR inhibitor and a hypomethylating agent in relapsed/ refractory AML. A more potent mTOR inhibitor, would be tolerable and effective at augmenting the activity of hypomethylating agents in AML, we report a dose-finding study of azacitidine in combination with the rapamycin derivative everolimus in relapsed and refractory AML

RESULTS

DISCUSSION

MATERIALS AND METHODS

Study design and treatment

Objectives and endpoints