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Blood. 2014 Oct 2;124(14):2190-5. doi: 10.1182/blood-2014-03-559963. Epub 2014 Jul 29.

The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma.

Author information

1
Alfred Hospital-Monash University, Melbourne, Australia;
2
Seoul National University Hospital, Seoul, South Korea;
3
Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; Melbourne University, Parkville, Australia;
4
GlaxoSmithKline Research and Development, Research Triangle Park, NC;
5
GlaxoSmithKline Research and Development, Philadelphia, PA; and.
6
Princess Margaret Hospital, Toronto, ON, Canada.

Abstract

The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib-an oral AKT inhibitor-in patients with advanced hematologic malignancies. Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6%), diarrhea (32.9%), and dyspepsia (24.7%). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at > 75-mg doses; the median time to peak plasma concentrations was 1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan's cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00881946.

Comment in

PMID:
25075128
PMCID:
PMC4229853
DOI:
10.1182/blood-2014-03-559963
[Indexed for MEDLINE]
Free PMC Article

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