The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study
Metrics: PDF 2033 views | HTML 2726 views | ?
Peter Tan1, Ing Soo Tiong1,2, Shaun Fleming1, Giovanna Pomilio2, Nik Cummings3, Mark Droogleever4, Julie McManus3, Anthony Schwarer5, John Catalano6, Sushrut Patil1, Sharon Avery1, Andrew Spencer1,2 and Andrew Wei1,2
1Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia
2Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
3Department of Pathology, Alfred Hospital, Melbourne, Australia
4Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands
5Eastern Health Clinical School, Monash University, Box Hill, Australia
6Clinical Haematology, Frankston Hospital, Frankston, Australia
Andrew Wei, email: email@example.com
Keywords: acute myeloid leukemia, everolimus, azacitidine, mTOR, clinical trial
Received: October 21, 2016 Accepted: November 20, 2016 Published: November 29, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.