RÉSUMÉ
CFI-400945 is a selective oral polo-like kinase 4 (PLK4) inhibitor that regulates centriole duplication. PLK4 is aberrantly expressed in patients with acute myeloid leukemia (AML). Preclinical studies indicate that CFI-400945 has potent in vivo efficacy in hematological malignancies and xenograft models, with activity in cells harboring TP53 mutations. In this phase 1 study in very high-risk patients with relapsed/refractory AML and myelodysplastic syndrome (MDS) (NCT03187288), 13 patients were treated with CFI-400945 continuously in dose escalation from 64 mg/day to 128 mg/day. Three of the 9 efficacy evaluable AML patients achieved complete remission (CR). Two of 4 AML patients (50%) with TP53 mutations and complex monosomal karyotype achieved a CR with 1 patient proceeding to allogenic stem cell transplant. A third patient with TP53 mutated AML had a significant reduction in marrow blasts by > 50% with an improvement in neutrophil and platelet counts. Responses were observed after 1 cycle of therapy. Dose-limiting toxicity was enteritis/colitis. A monotherapy and combination therapy study with a newer crystal form of CFI-400945 in patients with AML, MDS and chronic myelomonocytic leukemia (CMML) is ongoing (NCT04730258).