Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination with Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia

The nuclear export protein XPO1 is overexpressed in many malignancies. In Acute Myeloid Leukemia (AML), elevated levels of XPO1 is also associated with poor prognosis. Clearly, the targeting of XPO1 is of clinical use in treating AML patients. However, according to R. Lapalombella et al., the current XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Consequently, in an attempt to overcome the problem of toxicity, small molecule Selective Inhibitors of Nuclear Exports (SINEs) were designed that specifically inhibit XPO1.¹

Selinexor is an orally bioavailable, slowly reversible SINE compound that specifically blocks XPO1 which has demonstrated anti-leukemic activity in AML cell lines. T. B. Alexander et al. conducted a phase 1 study of selinexor in combination with fludarabine and cytarabine in 18 pediatric relapsed or refractory (R/R) Acute Leukemia patients. The study was published in the Journal of Clinical Oncology in August 2016. The key published results were as follows:

• In terms of toxicity, asymptomatic hyponatremia was the most frequent adverse event associated with selinexor (median sodium nadir, 128.5 meq/L; range, 123 to 132 meq/L).
• Pancytopenia was observed after initial dosing of selinexor in all 16 patients whom had received fludarabine and cytarabine.
• In terms of efficacy, after the completion of one course of combination therapy, 7 of 15 evaluable patients (47%) achieved CR or CRi, including five who had no detectable Minimal Residual Disease (MRD).
• Morphological changes indicating myeloid differentiation were observed in bone marrow aspirations of 3 patients (see figure1).

Conclusion

Despite the small cohort of patients included in this study, the authors concluded that selinexor in combination with fludarabine and cytarabine, was tolerated at doses up to 55 mg/m2 in pediatric patients with R/R Acute Leukemia

The study was registered at https://clinicaltrials.gov/: NCT02212561.

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 2g/m2 were administered on days 15to19. 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 non-hematologic toxicity was asymptomatic hyponatremia. Two patients who were treated at 70mg/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 pre-treated, 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.