Final Results of Phase I/II Study of Selinexor (SEL) with Sorafenib in Patients (pts) with Relapsed and/or Refractory (R/R) FLT3 Mutated Acute Myeloid Leukemia (AML)

Responses to FLT3-inhibitors are usually transient due to emergence of resistance through the acquisition of kinase domain point mutations and other non-mutational mechanisms. SEL is a potent first-in-class Selective Inhibitor of Nuclear Export/SINE™ that exerted marked cell killing of human and murine FLT3-mutant AML cells, including those with ITD, D835Y, ITD+Y842C or ITD+F691L mutations by modulating the cdk inhibitor p27 and anti-apoptotic Mcl-1. The combination of SEL+sorafenib had synergistic pro-apoptotic effects in FLT3-mutated AML cells by suppressing phosphorylation levels of FLT3 and its downstream signaling mediators ERK/AKT, and by inducing myeloid differentiation in ITD and D835 mutated cell lines. We designed a phase I/II trial of SEL with sorafenib for FLT3-ITD and/or -D835 R/R AML pts. In phase I, the primary objectives were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and dose-limiting toxicity (DLT) of the combination. In phase II, primary objectives included the rate of composite complete remission (CRc) defined as CR+CR with incomplete platelet recovery (CRp)+CR with incomplete count recovery (CRi) within 3 months (mos) of therapy initiation. Secondary objectives were safety and overall survival (OS). SEL was given orally twice a week for 3-weeks on and 1-week off in 28-day cycles and sorafenib was given continuously at a dose of 400mg twice daily from cycle 1 day 1 of SEL. In phase I, SEL dose was de-escalated in “3+3” fashion starting at dose level 0 and going down if DLTs were exceeded (dose levels 0, -1, -2 = 80, 60, 40 mg, respectively). Once MTD was established, the phase II enrolled pts in 2 cohorts: prior FLT3-inhibitor failure (cohort 1) and FLT3-inhibitor naïve (cohort 2). PB or BM samples were collected at pre-dose (C1D1), 24 h (C1D2) and day 28 (C1D28) of cycle 1, and apoptosis induction was determined by measuring annexin V positivity with FACS. 17 pts with median (med) age of 68 yrs (range 24-81) were enrolled. All pts had baseline next generation sequencing for AML specific mutations (Fig 1A). Median number of prior therapies was 3 (range, 1-6) as follows: salvage (S) 1: n=1, S2: n=7, S3+: n=9. 12 (71%) pts had prior FLT3-inhibitor exposure: 1 prior FLT3-inhibitor (n=10); 2 prior FLT3-inhibitors: n= (2). Four pts had prior allogeneic stem cell transplant. Four pts were treated at dose level 0 (SEL 80mg) with DLTs in 2 (Grade (G) 3 sepsis, n=1; G3 mucositis, syncope, adrenal insuffic