Leijen Suzanne, van Geel Robin M J M, Pavlick Anna C, Tibes Raoul, Rosen Lee, Razak Albiruni R Abdul, Lam Raymond, Demuth Tim, Rose Shelonitda, Lee Mark A, Freshwater Tomoko, Shumway Stuart, Liang Li Wen, Oza Amit M, Schellens Jan H M, Shapiro Geoffrey I
Suzanne Leijen, Robin M.J.M. van Geel, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; Anna C. Pavlick, New York University Medical Center, New York, NY; Lee Rosen, University of California Los Angeles, Santa Monica, CA; Raymond Lam, Shelonitda Rose, Mark A. Lee, Tomoko Freshwater, and Stuart Shumway, Merck, Kenilworth, NJ; Geoffrey I. Shapiro, Dana-Farber Cancer Institute, Boston, MA; Albiruni R. Abdul Razak and Amit M. Oza, Princess Margaret Hospital, Toronto, Ontario, Canada; Raoul Tibes, University Hospital of Würzburg, Würzburg; Tim Demuth, Sandoz AG, Holzkirchen, Germany; and Li Wen Liang, Merck Sharp & Dohme R&D, Beijing, China.
J Clin Oncol. 2016 Dec 20;34(36):4371-4380. doi: 10.1200/JCO.2016.67.5991. Epub 2016 Oct 31.
Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient tumor cells to DNA damage. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZD1775 as monotherapy or in combination with chemotherapy in patients with refractory solid tumors. Patients and Methods In part 1, patients received a single dose of AZD1775 followed by 14 days of observation. In part 2, patients received AZD1775 as a single dose (part 2A) or as five twice per day doses or two once per day doses (part 2B) in combination with one of the following chemotherapy agents: gemcitabine (1,000 mg/m), cisplatin (75 mg/m), or carboplatin (area under the curve, 5 mg/mL⋅min). Skin biopsies were collected for pharmacodynamic assessments. TP53 status was determined retrospectively in archival tumor tissue. Results Two hundred two patients were enrolled onto the study, including nine patients in part 1, 43 in part 2A (including eight rollover patients from part 1), and 158 in part 2B. AZD1775 monotherapy given as single dose was well tolerated, and the maximum-tolerated dose was not reached. In the combination regimens, the most common adverse events consisted of fatigue, nausea and vomiting, diarrhea, and hematologic toxicity. The maximum-tolerated doses and biologically effective doses were established for each combination. Target engagement, as a predefined 50% pCDK1 reduction in surrogate tissue, was observed in combination with cisplatin and carboplatin. Of 176 patients evaluable for efficacy, 94 (53%) had stable disease as best response, and 17 (10%) achieved a partial response. The response rate in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33). Conclusion AZD1775 was safe and tolerable as a single agent and in combination with chemotherapy at doses associated with target engagement.
AZD1775是一种靶向G2检查点控制的WEE1激酶抑制剂，优先使TP53缺陷的肿瘤细胞对DNA损伤敏感。这项I期研究评估了口服AZD1775单药治疗或与化疗联合治疗难治性实体瘤患者的安全性、耐受性、药代动力学和药效学。
在第1部分中，患者接受单剂量AZD1775，随后观察14天。在第2部分中，患者接受AZD1775单剂量（第2A部分）或每天两次共五次剂量或每天一次共两次剂量（第2B部分），并与以下化疗药物之一联合使用：吉西他滨（1000mg/m²）、顺铂（75mg/m²）或卡铂（曲线下面积，5mg/mL·min）。采集皮肤活检样本进行药效学评估。在存档肿瘤组织中回顾性确定TP53状态。
202例患者入组本研究，包括第1部分的9例患者、第2A部分的43例患者（包括第1部分的8例转入患者）和第2B部分的158例患者。单剂量给予AZD1775单药治疗耐受性良好，未达到最大耐受剂量。在联合治疗方案中，最常见的不良事件包括疲劳、恶心和呕吐、腹泻以及血液学毒性。确定了每种联合治疗的最大耐受剂量和生物学有效剂量。与顺铂和卡铂联合使用时，观察到靶点参与，即替代组织中pCDK1降低50%这一预定义情况。在176例可评估疗效的患者中，94例（53%）最佳反应为疾病稳定，17例（10%）达到部分缓解。TP53突变患者（n = 19）的缓解率为21%，而TP53野生型患者（n = 33）为12%。
AZD1775作为单药以及与化疗联合使用时，在与靶点参与相关的剂量下是安全且可耐受的。
