Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Cancer. 2019 Aug 15;125(16):2837-2845. doi: 10.1002/cncr.32138. Epub 2019 Apr 23.
Epigenetic abnormalities are manifold in all solid tumors and include changes in chromatin configuration and DNA methylation. The authors designed a phase 1 study to evaluate the oral DNA methyltransferase inhibitor CC-486 combined with the histone deacetylase inhibitor romidepsin in advanced solid tumors with dose expansion to further evaluate pharmacodynamics and possible clinical benefit of the recommended phase 2 dose (RP2D).
This was a phase 1 study with a 3 + 3 dose-escalation design and an expansion phase for patients with virally mediated cancers. The disease control rate (DCR) was the primary outcome for the expansion cohort. Correlative studies included long interspersed nucleotide element 1 (LINE-1) methylation and drug exposure in blood samples (clinicaltrials.gov identifier NCT01537744).
Fourteen patients were enrolled in the dose-escalation portion at 3 dose levels. Three patients experienced dose-limiting toxicities; the RP2D was oral CC-486 300 mg daily on days 1 through 14 and romidepsin 8 mg/m on days 8 and 15. Because of slow accrual into the expansion phase, the trial was closed after 4 patients enrolled. Common toxicities of the combination included nausea (83.3%), anorexia (72.2%), fatigue (61.1%), and constipation (55.6%). There were 12 patients evaluable for response, 5 with stable disease, of whom 2 received >4 cycles; there were no responses. Exposure to CC-486 and romidepsin was consistent with prior data. LINE-1 methylation on C1D8 was significantly reduced (mean, -6.23; 95% CI, -12.23, -0.24; P = .04).
Although, at the RP2D, the combination of CC-486 and romidepsin was tolerable, no significant anticancer activity was observed. Significant demethylation in post-treatment circulating tumor DNA and biopsies provided proof of target acquisition.
表观遗传异常在所有实体肿瘤中都存在多种表现,包括染色质构象和 DNA 甲基化的改变。作者设计了一项 1 期研究,以评估口服 DNA 甲基转移酶抑制剂 CC-486 联合组蛋白去乙酰化酶抑制剂罗米地辛治疗晚期实体瘤,剂量扩展以进一步评估推荐的 2 期剂量(RP2D)的药效学和可能的临床获益。
这是一项 1 期研究,采用 3+3 剂量递增设计和病毒介导癌症患者的扩展阶段。扩展队列的主要终点是疾病控制率(DCR)。相关研究包括长散布核元件 1(LINE-1)甲基化和血液样本中的药物暴露(临床试验.gov 标识符 NCT01537744)。
在 3 个剂量水平上共招募了 14 名患者进入剂量递增部分。3 名患者出现剂量限制毒性;RP2D 为口服 CC-486 300mg,每日 1 次,连用 14 天,罗米地辛 8mg/m,连用 15 天。由于扩展阶段入组速度较慢,该试验在入组 4 例患者后关闭。联合用药的常见毒性包括恶心(83.3%)、厌食(72.2%)、疲劳(61.1%)和便秘(55.6%)。12 名患者可评估反应,5 名患者病情稳定,其中 2 名患者接受了>4 个周期的治疗;无反应。CC-486 和罗米地辛的暴露情况与先前的数据一致。C1D8 的 LINE-1 甲基化显著降低(平均,-6.23;95%CI,-12.23,-0.24;P=0.04)。
尽管在 RP2D 时,CC-486 和罗米地辛联合治疗是可耐受的,但未观察到明显的抗癌活性。治疗后循环肿瘤 DNA 和活检中的显著去甲基化提供了获得靶标的证据。