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/m2 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/m2 and cytarabine 2 g/m2 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. 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/m2 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. Conclusion Selinexor, in combination with fludarabine and cytarabine, is tolerable at doses up to 55 mg/m2 in pediatric patients with relapsed or refractory leukemia. All patients who received selinexor at ≥ 40 mg/m2 demonstrated XPO1 target inhibition. Response rates are promising and will be further explored in a phase II trial.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org.

Figures

Fig 1.

Axial T2-weighted magnetic resonance imaging scan of (A and B) the two patients with dose-limiting toxicity at 70 mg/m2. Both patients show diffuse cerebellar edema and hyperintensity (white arrows), sparing the brainstem (blue arrows), deep cerebellar nuclei, and cerebrum.

Fig 2.

Mean plasma selinexor concentration in pediatric patients at day 1 showed little separation between the 30 and 40 mg/m2 dose levels, with an increase in exposure evident at the 55 and 70 mg/m2 dose levels. Mean plasma selinexor concentration in pediatric patients after the day-22 dose showed peak levels and dynamics similar to the day-1 levels.

Fig 3.

XPO1 mRNA expression levels by dose. Inhibition of XPO1 was assessed by quantitative reverse transcription-polymer chain reaction of XPO1, which is upregulated at the RNA level in response to XPO1 protein inactivation.

Fig 4.

Bone marrow aspirates of patient No. 5: (A) before therapy, showing myeloblasts along with neutrophils, myelocytes, and promyelocytes; and (B) at day 15, showing differentiation evidenced by the absence of blasts, with an increase in neutrophils and myelocytes. Bone marrow aspirates of patient No. 14: (C) before therapy, showing monoblasts and occasional neutrophils; and (D) at day 15, showing a decrease in monoblasts with a corresponding increase in immature promonocytes.