A phase IIa study of afuresertib, an oral pan-AKT inhibitor, in patients with Langerhans cell histiocytosis.
Langerhans cell histiocytosis (LCH) is a clonal neoplasm characterized by widely varied clinical presentations, including multisystem involvement and systemic inflammatory symptoms. The AKT pathway is relevant to survival and proliferation of dendritic cells, and is also often upregulated in hematopoietic malignancies. A clinical response in an adult patient with LCH participating in the first-in-human trial of afuresertib prompted this prospective trial.



The population in the current study included treatment-naïve (n = 7) and recurrent/refractory patients with LCH (n = 10), who received oral afuresertib (125 mg). The majority of patients were treated for > 24 weeks, with four patients receiving treatment for > 48 weeks.



Pharmacokinetic analysis showed similar exposures in previously reported patients with other hematologic malignancies. Primary drug-related toxicities included Grade 1/2 nausea, diarrhea, dyspepsia, and vomiting. Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis. The overall response rate in evaluable subjects was 33% in treatment-naïve patients and 28% in patients with recurrent/refractory disease, which did not meet the predefined Bayesian criteria for efficacy.



Afuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.
Department of Child Health, University of Arizona College of Medicine, Phoenix, Ronald Matricaria Institute of Molecular, Medicine at Phoenix Children's Hospital, Phoenix, Arizona, USA.
Robert J
RJ
Arceci
Section of Hematology-Oncology, Department of Pediatrics, Texas Children's Hospital, Feigin Research Center, Baylor College of Medicine, Houston, Texas.
Carl E
CE
Allen
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
Ira J
IJ
Dunkel
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Eric
E
Jacobsen
Department of Hematology/Oncology, The Hospital for Sick Children, Ontario, Toronto, Canada.
James
J
Whitlock
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.
Robert
R
Vassallo
GlaxoSmithKline, Research Triangle Park, North Carolina.|MedImmune, Inc., Gaithersburg, Maryland.
Shannon R
SR
Morris
GlaxoSmithKline, King of Prussia, Pennsylvania.|ADP Consulting, LLC, Baton Rouge, Louisiana.
Alison
A
Portnoy
GlaxoSmithKline, King of Prussia, Pennsylvania.
Beth Ann
BA
Reedy
GlaxoSmithKline, Research Triangle Park, North Carolina.|Parexel International, Durham, North Carolina.
Deborah A
DA
Smith
GlaxoSmithKline, King of Prussia, Pennsylvania.
Robert
R
Noble
GlaxoSmithKline, King of Prussia, Pennsylvania.
Amy
A
Murnane
GlaxoSmithKline, Collegeville, Pennsylvania.|Idera Pharmaceuticals, Exton, Pennsylvania.
Mark
M
Cornfeld
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Carlos
C
Rodriguez-Galindo
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.|Department of Hematology, Columbia University Medical Center, USA.
Mark L
ML
Heaney
Section of Hematology-Oncology, Department of Pediatrics, Texas Children's Hospital, Feigin Research Center, Baylor College of Medicine, Houston, Texas.
Kenneth
K
McClain
Pediatric Hematology-Oncology Department, Staten Island University Hospital, Staten Island, New York.
Sarah
S
Vaiselbuh
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006646:Histiocytosis, Langerhans-Cell / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014481:United States
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; C000593263:afuresertib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt
AKT inhibitor; Langerhans cell histiocytosis; afuresertib