A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia

Abstract

Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 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 a 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 nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m) 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 blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.

Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

“…In summary, KPT‐330 synergizes with ABT‐199 to induce apoptosis in AML cell lines and primary patient samples at clinically relevant concentrations . Both Bcl‐2 and XPO1 are up‐regulated in LSCs and their inhibition by ABT‐199 and KPT‐330, respectively, can selectively target LSCs .…”

Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates

“…Underscoring this theme, corepressors (e.g., DNMT1) that oppose coactivators to repress rather than activate genes were enriched in the protein interactomes of nuclear CEBPA and RUNX1 in NPM1-mutated AML cells, and altogether more than 500 granulocyte and monocyte terminal differentiation genes were repressed. We showed previously that PU.1 and RUNX1 collaborate by excluding corepressors and recruiting coactivators (20,21), a motif akin to corepressor/coactivator exchange at nuclear receptors upon bindselinexor (KPT330) has been evaluated in unselected AML genotypes and with traditional cytotoxic intent -dosages were escalated toward maximum tolerated levels of approximately 55-70 mg/m 2 (93.5-119 mg fixed doses) and administered 1-2 times per week in 3-to 4-week cycles, to achieve plasma C max greater than 700 nM (54,56,57,86), leading to a recommended phase II dose of 60 mg (~35 mg/m 2 ) twice per week in 4-week cycles. The molecular mechanism information in this report suggests an alternative application of selinexor or its more potent analogs that selects for patients with refractory/relapsed NPM1-mutated AML and then uses substantially lower, better-tolerated doses for a defined molecular pharmacodynamic objective of locking PU.1 in the nucleus, and for a downstream pathway objective of activating monocytic terminal differentiation -cell cycle exits by terminal differentiation can spare normal HSCs (good therapeutic index) and do not require the master transcription factor regulator of apoptosis (cytotoxicity) p53 (40,63,65,67,87).…”

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). Several doses and administration schedules were tested.…”