EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Final Results of Dose Escalation and Optimization Cohorts from a Phase I/IIa Study in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML) or Myelodysplastic Syndrome (MDS)

Background

Aurora kinases are implicated in the development of resistance to FLT3 inhibitors (Joshi S et al. Cancer Cell 2021;39:999–1014); and dual inhibition of FLT3 and Aurora kinase has been shown to overcome acquired resistance to selective FLT3 inhibition both in vitro and in vivo (Moore A et al. Leukemia 2012;26:1462–70; Tariq M et al. Br J Cancer 2021;125:966–74). Here we present the final data generated from the dose escalation and optimization cohorts from a Phase I/IIa study of EP0042.

Methods

The primary objective of the dose escalation and optimization cohorts of this multi-center study was to investigate safety/tolerability and to establish both the MTD and optimal dose of EP0042 when used as a monotherapy in patients (pts) with R/R AML, CMML or MDS. Secondary objectives included PK characterization and assessment of anti-tumor activity.

Results

A total of 46 pts (20 f/26 m) with R/R AML (33), CMML (2) or MDS (11) were enrolled, with a median age of 72 years, ranging from 25-84 years. FLT3 Status at screening: FLT3-ITD (10), FLT3-TKD (1), Wild Type (35). The median number of prior treatments was 2 (range 1-6).13 pts received a prior FLT3 inhibitor (midostaurin, gilteritinib, sorafenib), with 10 receiving ≥2 inhibitors.

Total daily doses ranging from 40 mg to 340 mg, administered QD or BID, on various schedules across 9 cohorts. Each cycle was 28 days. Dose escalation in 7 cohorts identified 150 mg BID as the MTD, with 2 pts experiencing DLTs (Grade 3 encephalopathy and somnolence/ataxia). Cohorts 8 (100mg BID) and 9 (140mg BID) were initiated for dose optimization and to identify an appropriate dose to study in combination with other therapies. Cohort 8 included 8 pts (6 evaluable for DLT), 2 experiencing Grade 3 ataxia. Cohort 9 included 6 pts (all evaluable), with 2 experiencing DLTs. All neurological events including ataxia, somnolence and encephalopathy were reversible after a short period of treatment interruption.

The most common treatment-emergent adverse events ≥20% were: diarrhea (61%), fatigue (52%), febrile neutropenia (50%), decreased appetite (39%), dyspnea (35%), ataxia (30%), nausea (30%), somnolence (28%), constipation (28%) and dizziness (20%). 24% of TEAEs were > grade 3. The most common AEs considered treatment-related ≥10% were: diarrhea (30%), ataxia (30%), somnolence (28%), fatigue (26%), decreased appetite (26%), dizziness (17%), nausea (15%), constipation (11%) and stomatitis (11%). There was a trend towards increased incidences at higher doses. Most events were manageable by temporary dose reductions and or/short interruptions. No treatment-related deaths have been reported.

PK evaluations indicate that 100mg BID is optimum with free plasma concentrations reaching EC50s for relevant kinases, and no increase in exposure at higher doses.

Across all cohorts, 25 pts achieved SD. Two notable cases included: (i) a pt (150 mg BID) who achieved CR MRD- confirmed by flow cytometry. This pt completed treatment on C15D15 and maintained transfusion independence for 10 months; and (ii) a pt (100 mg BID) who achieved MLFS on C2D1 and remained in the trial until C4D22. This pt required ongoing transfusions and discontinued the trial due to thrombocytopenia. In addition, 5 pts (11%) experienced a ≥ 50% reduction in peripheral blasts during treatment.

Conclusions

EP0042 has an acceptable and manageable safety profile with encouraging evidence of activity in heavily pretreated pts. The 100 mg BID dose schedule has been selected for further evaluation based on tolerability, safety, PK and evidence of efficacy. A further module will assess the combination of EP0042 with venetoclax and azacitidine - preliminary data will be presented at the conference.