title: The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma.
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.
authors: Alfred Hospital-Monash University, Melbourne, Australia;
authors: Andrew
authors: A
authors: Spencer
authors: Seoul National University Hospital, Seoul, South Korea;
authors: Sung-Soo
authors: SS
authors: Yoon
authors: Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; Melbourne University, Parkville, Australia;
authors: Simon J
authors: SJ
authors: Harrison
authors: GlaxoSmithKline Research and Development, Research Triangle Park, NC;
authors: Shannon R
authors: SR
authors: Morris
authors: GlaxoSmithKline Research and Development, Research Triangle Park, NC;
authors: Deborah A
authors: DA
authors: Smith
authors: GlaxoSmithKline Research and Development, Philadelphia, PA; and.
authors: Richard A
authors: RA
authors: Brigandi
authors: GlaxoSmithKline Research and Development, Research Triangle Park, NC;
authors: Jennifer
authors: J
authors: Gauvin
authors: GlaxoSmithKline Research and Development, Philadelphia, PA; and.
authors: Rakesh
authors: R
authors: Kumar
authors: GlaxoSmithKline Research and Development, Philadelphia, PA; and.
authors: Joanna B
authors: JB
authors: Opalinska
authors: Princess Margaret Hospital, Toronto, ON, Canada.
authors: Christine
authors: C
authors: Chen
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D061214:Patient Safety; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; C000593263:afuresertib; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt