title: Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia.
abstract: Purpose To characterize the toxicity, pharmacokinetics, and pharmacodynamics of selinexor, a selective inhibitor of nuclear export, when combined with fludarabine and cytarabine, in children with relapsed or refractory leukemia. Patients and Methods Eighteen patients with relapsed or refractory acute leukemia were enrolled in the SELHEM (Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome) clinical trial (NCT02212561). Selinexor, initially at 30 mg/m2per dose, was given orally on days 1, 3, 8, 10, 22, and 24 and was escalated according to a rolling-six design. Fludarabine 30 mg/m2and cytarabine 2 g/m2were administered on days 15 to 19. Pharmacokinetic and pharmacodynamic studies were performed on days 1 and 22. Response evaluations were performed on day 15 and at the completion of course 1. Results Among the 17 patients who were evaluable for toxicity, three were treated at 30 mg/m2, three at 40 mg/m2, six at 55 mg/m2, and five at 70 mg/m2. The most common grade 3 nonhematologic toxicity was asymptomatic hyponatremia. Two patients who were treated at 70 mg/m2experienced reversible cerebellar toxicity, thereby defining the dose-limiting toxicity. Pharmacokinetic parameters demonstrated that plasma exposure was dose proportional. Fifteen of 16 patients demonstrated at least a twofold increase of XPO1 mRNA, indicating inhibition of the XPO1 protein. In this group of heavily pretreated, relapsed, and refractory patients, seven of 15 evaluable patients (47%) achieved complete response or complete response with incomplete count recovery. Conclusion Selinexor, in combination with fludarabine and cytarabine, is tolerable at doses up to 55 mg/m2in pediatric patients with relapsed or refractory leukemia. All patients who received selinexor at ≥ 40 mg/m2demonstrated XPO1 target inhibition. Response rates are promising and will be further explored in a phase II trial.
authors: Thomas B. Alexander, John K. Choi, Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, St Jude Children's Research Hospital; Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, University of Tennessee College of Medicine, Memphis, TN; and Norman J. Lacayo, Lucile Packard Children's Hospital Stanford, Stanford, CA.
authors: Thomas B
authors: TB
authors: Alexander
authors: Thomas B. Alexander, John K. Choi, Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, St Jude Children's Research Hospital; Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, University of Tennessee College of Medicine, Memphis, TN; and Norman J. Lacayo, Lucile Packard Children's Hospital Stanford, Stanford, CA.
authors: Norman J
authors: NJ
authors: Lacayo
authors: Thomas B. Alexander, John K. Choi, Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, St Jude Children's Research Hospital; Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, University of Tennessee College of Medicine, Memphis, TN; and Norman J. Lacayo, Lucile Packard Children's Hospital Stanford, Stanford, CA.
authors: John K
authors: JK
authors: Choi
authors: Thomas B. Alexander, John K. Choi, Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, St Jude Children's Research Hospital; Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, University of Tennessee College of Medicine, Memphis, TN; and Norman J. Lacayo, Lucile Packard Children's Hospital Stanford, Stanford, CA.
authors: Raul C
authors: RC
authors: Ribeiro
authors: Thomas B. Alexander, John K. Choi, Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, St Jude Children's Research Hospital; Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, University of Tennessee College of Medicine, Memphis, TN; and Norman J. Lacayo, Lucile Packard Children's Hospital Stanford, Stanford, CA.
authors: Ching-Hon
authors: CH
authors: Pui
authors: Thomas B. Alexander, John K. Choi, Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, St Jude Children's Research Hospital; Raul C. Ribeiro, Ching-Hon Pui, and Jeffrey E. Rubnitz, University of Tennessee College of Medicine, Memphis, TN; and Norman J. Lacayo, Lucile Packard Children's Hospital Stanford, Stanford, CA.
authors: Jeffrey E
authors: JE
authors: Rubnitz
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000208:Acute Disease; D000284:Administration, Oral; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D007223:Infant; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D012008:Recurrence; D012074:Remission Induction; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D006834:Hydrazines; D014230:Triazoles; D003561:Cytarabine; C585161:selinexor; D014740:Vidarabine; C024352:fludarabine