BACKGROUND Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. PATIENTS AND METHODS In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. RESULTS Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. CONCLUSION GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. CLINICAL TRIAL NUMBER NCT01564251.

中文翻译：

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难治性实体瘤患者中检查点激酶1抑制剂GDC-0575联合吉西他滨的I期研究。

背景技术化疗引起的DNA损伤后对Checkpoint激酶1（Chk1）的抑制作用会超越细胞周期阻滞，并导致有丝分裂灾难和细胞死亡。GDC-0575是一种高度选择性的口服小分子Chk1抑制剂，可在异种移植模型中导致肿瘤缩小和生长延迟。我们评估了单独和与吉西他滨联用的GDC-0575的安全性，耐受性和药代动力学特性。评估抗肿瘤活性和Chk1途径调节。患者和方法在第一阶段开放标签研究中，在剂量递增阶段，将患者纳入GDC-0575单药治疗组（1）或GDC-0575与吉西他滨治疗组（2）的组合，以确定最大耐受剂量。第2组的患者接受静脉吉西他滨1000 mg / m2（第2a组）或500 mg / m2（第2b组）静脉注射，随后接受GDC-0575（45或80 mg，分别作为RP2D）。第二阶段纳入了疾病特异性队列。结果在102例接受治疗的患者中，女性占70％，中位年龄为59岁（范围27-85），东部合作肿瘤小组PS 0为47％。最常见的肿瘤类型为乳腺癌（37％）。与GDC-0575和/或吉西他滨相关的最常见不良事件（所有级别）是中性粒细胞减少症（68％），贫血（48％），恶心（43％），疲劳（42％）和血小板减少症（35％）。GDC-0575的最大浓度在给药后2小时内达到，半衰期约为23小时。在GDC-0575和吉西他滨之间未观察到药代动力学药物相互作用。在接受GDC-0575和吉西他滨治疗的患者中，有四个确诊的部分反应，其中三个发生在具有TP53突变的肿瘤患者中。药效学数据与GDC-0575抑制吉西他滨诱导的pCDK1 / 2表达一致。结论GDC-0575可单药安全地与吉西他滨联用。但是，吉西他滨的总体耐受性中等。血液学毒性很常见，但可以控制。观察到初步的抗肿瘤活性，但仅限于少数使用GDC-0575和吉西他滨治疗的难治性实体瘤患者。临床试验号NCT01564251。观察到初步的抗肿瘤活性，但仅限于少数使用GDC-0575和吉西他滨治疗的难治性实体瘤患者。临床试验号NCT01564251。观察到初步的抗肿瘤活性，但仅限于少数使用GDC-0575和吉西他滨治疗的难治性实体瘤患者。临床试验号NCT01564251。