Do Khanh, Wilsker Deborah, Ji Jiuping, Zlott Jennifer, Freshwater Tomoko, Kinders Robert J, Collins Jerry, Chen Alice P, Doroshow James H, Kummar Shivaani
Khanh Do, Jennifer Zlott, Jerry Collins, Alice P. Chen, James H. Doroshow, and Shivaani Kummar, National Cancer Institute, Bethesda, MD; Deborah Wilsker, Jiuping Ji, and Robert J. Kinders, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and Tomoko Freshwater, Merck Research Laboratories-Oncology, Boston, MA.
J Clin Oncol. 2015 Oct 20;33(30):3409-15. doi: 10.1200/JCO.2014.60.4009. Epub 2015 May 11.
Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies.
AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3 + 3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD.
Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in γH2AX levels (three of five paired biopsies) were demonstrated.
This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies.
Wee1酪氨酸激酶在DNA损伤时使细胞周期蛋白依赖性激酶（Cdk）1/2磷酸化并使其失活。AZD1775是首个Wee1激酶抑制剂，在临床前模型中具有单药抗肿瘤活性。我们开展了一项针对难治性实体瘤成年患者的AZD1775单药I期研究，以确定其最大耐受剂量（MTD）、药代动力学以及配对肿瘤活检中磷酸化酪氨酸15 - Cdk（pY15 - Cdk）和磷酸化组蛋白H2AX（γH2AX）水平的变化情况。
AZD1775每周2.5天，每天口服两次，每21天周期给药最多2周（3 + 3设计）。在MTD剂量下，于基线和第5次给药后获取配对肿瘤活检样本，以测定pY15 - Cdk和γH₂AX水平。6例携带BRCA突变的实体瘤患者也入组了MTD剂量研究。
共入组25例患者。确定的MTD为每周2.5天，每天口服225 mg，分两次服用，每21天周期给药2周。在两名携带BRCA突变的患者中观察到了确认的部分缓解：1例为头颈癌患者，1例为卵巢癌患者。常见毒性为骨髓抑制和腹泻。剂量限制性毒性为室上性快速心律失常和骨髓抑制。观察到药物蓄积（半衰期约11小时）。配对活检样本中显示pY15 - Cdk水平降低（5对活检样本中有2对），γH2AX水平升高（5对活检样本中有3对）。
这是关于AZD1775在携带BRCA突变患者中的单药活性的首份报告。通过配对肿瘤活检中的靶点调节和DNA损伤反应证明了作用机制。
