Abstract：
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).
摘要：
CFI-400945是一种选择性口服polo样激酶4（PLK4）抑制剂，可调节中心粒重复。PLK4在急性髓性白血病（AML）患者中异常表达。临床前研究表明，CFI-400945在血液恶性肿瘤和异种移植模型中具有有效的体内功效，在携带TP53突变的细胞中具有活性。在这项针对复发性/难治性AML和骨髓增生异常综合征（MDS）的高危患者的1期研究中（NCT03187288），用CFI-400945连续治疗13名患者,剂量从64mg/天递增至128mg/天。9例疗效可评估的AML患者中有3例达到完全缓解（CR）。4例具有TP53突变和复杂单体核型的AML患者中，有2例（50％）获得了CR，其中1例患者进行了同种异体干细胞移植。第三位TP53突变的AML患者骨髓母细胞显著减少>50%,中性粒细胞和血小板计数改善。治疗1个周期后观察到反应。剂量限制性毒性为肠炎/结肠炎。在AML患者中使用新的CFI-400945晶型进行的单药和联合治疗研究，MDS和慢性粒单核细胞白血病（CMML）正在进行中（NCT04730258）。
