Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia. The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0–2. In the dose escalation portion of the trial, patients received a starting dose of iadademstat at 90 μg/m per day (with de-escalation to 60 μg/m per day and escalation up to 140 μg/m per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m subcutaneously, for seven of 28 days. The primary objectives were safety (analysed in the safety analysis set; all patients who received at least one dose of study treatment) and establishing the recommended phase 2 dose; secondary objectives included response rates in the efficacy analysis set (all patients who had at least one efficacy assessment). This study is registered on EudraCT (EudraCT 2018-000482-36) and has been completed. Between Nov 12, 2018, and Sept 30, 2021, 36 patients with newly diagnosed acute myeloid leukaemia were enrolled; the median age was 76 (IQR 74–79) years, all patients were White, 18 (50%) were male, and 18 (50%) were female, and all had intermediate-risk or adverse-risk acute myeloid leukaemia. The median follow-up was 22 (IQR 16–31) months. The most frequent (≥10%) adverse events considered to be related to treatment were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3–4) and anaemia (15 [42%]; of which ten [28%] were grade 3–4). Three patients had treatment-related serious adverse events (one fatal grade 5 intracranial haemorrhage, one grade 3 differentiation syndrome, and one grade 3 febrile neutropenia). Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 μg/m per day with azacitidine. 22 (82%; 95% CI 62–94) of 27 patients in the efficacy analysis set had an objective response. 14 (52%) of 27 patients had complete remission or complete remission with incomplete haematological recovery; of these, ten of 11 evaluable for measurable residual disease achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an objective response. The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid leukaemia, including those with high-risk prognostic factors. Oryzon Genomics and Spain's Ministerio de Ciencia, Innovacion y Universidades (MICIU)-Agencia Estatal de Investigacion (AEI).

中文翻译：

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Iadademstat 联合阿扎胞苷治疗新诊断的急性髓系白血病 (ALICE) 患者：一项开放标签、2a 期剂量探索研究


Iadademstat 是一种有效的、选择性的口服抑制剂，可抑制转录抑制因子赖氨酸特异性去甲基化酶 1（LSD1；也称为 KDM1A）的酶活性和支架活性，在 1 期试验中显示出有希望的早期活性和安全性，并与其他药物具有强大的临床前协同作用。急性髓系白血病细胞系中的阿扎胞苷。因此，我们的目的是研究 iadademstat 和阿扎胞苷联合治疗新诊断的急性髓系白血病成人患者。开放标签、2a 期剂量探索 ALICE 研究在西班牙的六家医院进行，纳入了年龄为 18 岁或以上、新诊断为急性髓性白血病、不适合强化化疗且 ECOG 体力状态为 0-2 的患者。在试验的剂量递增部分，患者口服 iadademstat 起始剂量为 90 μg/m2（逐渐降低至每天 60 μg/m2，然后逐步增加至每天 140 μg/m2），持续 5 次。每周休息 2 天，皮下注射阿扎胞苷 75 mg/m2，连续 28 天中的 7 天。主要目标是安全性（在安全性分析集中进行分析；所有接受至少一剂研究治疗的患者）和确定推荐的 2 期剂量；次要目标包括功效分析组中的反应率（所有至少进行过一次功效评估的患者）。该研究已在EudraCT上注册（EudraCT 2018-000482-36）并已完成。 2018年11月12日至2021年9月30日期间，入组了36名新诊断的急性髓系白血病患者；中位年龄为 76 岁（IQR 74-79）岁，所有患者均为白人，其中 18 例（50%）为男性，18 例（50%）为女性，所有患者均患有中危或不良危急性髓系白血病。 中位随访时间为 22（IQR 16-31）个月。被认为与治疗相关的最常见（≥10%）不良事件是血小板（25 [69%]）和中性粒细胞（22 [61%]）计数减少（均为 3-4 级）和贫血（15 [42 %]；其中 10 名 [28%] 为 3-4 年级）。 3 名患者出现与治疗相关的严重不良事件（一名致命的 5 级颅内出血、一名 3 级分化综合征和一名 3 级发热性中性粒细胞减少症）。根据安全性、药代动力学和药效学数据以及疗效，iadademstat 的推荐 2 期剂量为每天 90 μg/m2 与阿扎胞苷。功效分析组中的 27 名患者中有 22 名（82%；95% CI 62-94）有客观缓解。 27 名患者中有 14 名（52%）获得完全缓解或完全缓解但血液学不完全恢复；其中，11 个可评估的可测量残留疾病中的 10 个达到了阴性。在安全性分析集中，36 名患者中有 22 名（61%）有客观缓解。 iadademstat 和阿扎胞苷的组合具有可控的安全性，并且对新诊断的急性髓性白血病患者（包括具有高风险预后因素的患者）显示出有希望的反应。 Oryzon Genomics 和西班牙科学、创新和大学部 (MICIU)-Agencia Estatal de Investigacion (AEI)。