Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Bethesda, MD, USA.
J Immunother Cancer. 2019 Jul 25;7(1):197. doi: 10.1186/s40425-019-0680-3.
Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1-3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable.
This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints.
Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2-6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not.
The RP2D is tolerable and has preliminary activity in recurrent women's cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients.
ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.
需要寻找提高免疫检查点抑制剂活性的策略。我们假设奥拉帕利（PARP 抑制剂）引起的 DNA 损伤增强和西地尼布（VEGFR1-3 抑制剂）减少的 VEGF 信号传导，将与 durvalumab（PD-L1 抑制剂）的抗肿瘤活性互补，并且三联药物组合是可耐受的。
这项 1 期研究通过 3+3 的剂量递增测试了三药联合治疗。西地尼布间歇性服用（5 天/2 天停药），剂量分别为 15 或 20mg（剂量水平 1 和 2），每 4 周静脉注射 durvalumab 1500mg，奥拉帕利片每日两次 300mg。主要终点是推荐的 2 期剂量（RP2D）。应答率、药代动力学（PK）和相关性分析是次要终点。
9 名患者（7 名卵巢癌/1 名子宫内膜癌/1 名三阴性乳腺癌，中位数为 3 种既往治疗[2-6]）接受了治疗。3/4 级不良事件包括高血压（9 例中的 1 例）、贫血（9 例中的 1 例）和淋巴细胞减少症（9 例中的 3 例）。没有患者出现剂量限制毒性。RP2D 是西地尼布，20mg（5 天/2 天停药），与 durvalumab 和奥拉帕利的全剂量联合使用。4 名患者有部分缓解（44%），3 名患者有持续≥6 个月的稳定疾病，临床获益率为 67%。未发现 durvalumab 存在、西地尼布或奥拉帕利联合用药对奥拉帕利或西地尼布 PK 参数有显著影响。肿瘤 PD-L1 表达与临床获益相关，但细胞因子和外周免疫亚群则无关。
RP2D 是可耐受的，在复发性女性癌症中具有初步疗效。一项针对复发性卵巢癌患者的 2 期扩展研究正在招募中。
ClinicalTrials.gov 标识符：NCT02484404。注册于 2015 年 6 月 29 日。
