Robert J Arceci1, Carl E Allen2, Ira J Dunkel3, Eric Jacobsen4, James Whitlock5, Robert Vassallo6, Shannon R Morris7,8, Alison Portnoy9,10, Beth Ann Reedy9, Deborah A Smith7,11, Robert Noble9, Amy Murnane9, Mark Cornfeld12,13, Carlos Rodriguez-Galindo4, Mark L Heaney3,14, Kenneth McClain2, Sarah Vaiselbuh15. 1. 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. 2. Section of Hematology-Oncology, Department of Pediatrics, Texas Children's Hospital, Feigin Research Center, Baylor College of Medicine, Houston, Texas. 3. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. 5. Department of Hematology/Oncology, The Hospital for Sick Children, Ontario, Toronto, Canada. 6. Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota. 7. GlaxoSmithKline, Research Triangle Park, North Carolina. 8. MedImmune, Inc., Gaithersburg, Maryland. 9. GlaxoSmithKline, King of Prussia, Pennsylvania. 10. ADP Consulting, LLC, Baton Rouge, Louisiana. 11. Parexel International, Durham, North Carolina. 12. GlaxoSmithKline, Collegeville, Pennsylvania. 13. Idera Pharmaceuticals, Exton, Pennsylvania. 14. Department of Hematology, Columbia University Medical Center, USA. 15. Pediatric Hematology-Oncology Department, Staten Island University Hospital, Staten Island, New York.
Abstract
BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSION: Afuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.
BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSION:Afuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.
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