A phase I clinical trial of single-agent selinexor in acute myeloid leukemia
Mené sur 95 patients atteints d'une leucémie myéloïde aiguë récidivante ou réfractaire, cet essai de phase I évalue la dose maximale tolérée, la toxicité et l'efficacité, du point de vue du taux de réponse objective, du sélinexor, un inhibiteur de la protéine XPO1, dispensé en monothérapie
Selinexor is a novel XPO1 inhibitor.Selinexor was safe and efficacious in relapsed or refractory AML. Selinexor is a novel, first-in-class, Selective Inhibitor of Nuclear Export (SINE) compound, which blocks XPO1 function, leads to nuclear accumulation of tumor suppressor proteins (TSPs) and induces cancer cell death. A phase I dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8 or 10 doses of selinexor in 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only non-hematologic, grade 3/4 AE occurring in >5% of the patient population was fatigue (14%). There were no reported DLTs or evidence of cumulative toxicity. The recommended phase 2 dose (RP2D) was established at 60mg (~35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow (BM) blasts from baseline. Patients achieving an OR had a significant improvement in median progression free survival (PFS) (5.1 vs 1.3 months, p=0.008, HR 3.1) and overall survival (OS) (9.7 vs 2.7 months, p=0.01, HR 3.1) compared to non-responders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase II clinical development.%U http://www.bloodjournal.org/content/bloodjournal/early/2017/03/23/blood-2016-11-750158.full.pdf