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

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 MethodsEighteen 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/m 2 per 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/m 2 and cytarabine 2 g/m 2 were 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. ResultsAmong the 17 patients who were evaluable for toxicity, three were treated at 30 mg/m 2 , three at 40 mg/m 2 , six at 55 mg/m 2 , and five at 70 mg/m 2 . The most common grade 3 nonhematologic toxicity was asymptomatic hyponatremia. Two patients who were treated at 70 mg/m 2 experienced 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. ConclusionSelinexor, in combination with fludarabine and cytarabine, is tolerable at doses up to 55 mg/m 2 in pediatric patients with relapsed or refractory leukemia. All patients who received selinexor at $ 40 mg/m 2 demonstrated XPO1 target inhibition. Response rates are promising and will be further explored in a phase II trial.

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

“…Alexander et al [195] Kuruvilla et al [196] evaluated Selinexor in 79 patients with different subtypes of non-Hodgkin lymphoma (NHL). In the dose-expansion phase of the study, Selinexor was administered at doses of 35 mg/m 2 or Garzon et al [197] carried out a phase I dose-escalation study in 95 patients with relapsed or refractory acute myeloid leukemia (AML).…”

Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis

“…In addition, alterations in the machinery regulating nuclear export globally have been observed in cancer. Notably, increased expression of XPO1 has been described in numerous can cers (13)(14)(15)(16), and many clinical trials have studied the efficacy of drugs inhibiting XPO1 in patients with cancer (16)(17)(18)(19)(20)(21).…”

A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone- and/or Enzalutamide-Refractory Metastatic Castration-Resistant Prostate Cancer

“…XPO‐1 inhibition with selinexor is being actively investigated in multiple solid and hematologic malignancies and has demonstrated promising clinical activity in advanced refractory hematologic malignancies in early phase trials, with response rates ranging from 30% to 50% . Although it is possible that differences in tissue distribution, tumor penetration, and biology across and within tumor types (i.e., differential dependence on XPO‐mediated nuclear export for survival) contribute to variations in clinical activity, pharmacodynamic studies evaluating XPO‐1 expression and clinical response were not performed in this study given early trial termination.…”