Mehta Minesh P, Wang Ding, Wang Fen, Kleinberg Lawrence, Brade Anthony, Robins H Ian, Turaka Aruna, Leahy Terri, Medina Diane, Xiong Hao, Mostafa Nael M, Dunbar Martin, Zhu Ming, Qian Jane, Holen Kyle, Giranda Vincent, Curran Walter J
Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene Street, GGK19, Baltimore, MD, 21201, USA,
J Neurooncol. 2015 Apr;122(2):409-17. doi: 10.1007/s11060-015-1733-1. Epub 2015 Feb 15.
Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood-brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10-300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9-13.5) and for the breast cancer subgroup was 7.7 mo (2.8-15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3-3.8) and 4.9 mo (4.2-5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.
维利帕尼是一种强效口服聚（ADP-核糖）聚合酶（PARP）抑制剂，可增强放射治疗的抗肿瘤活性并能穿过血脑屏障。这是一项1期剂量递增研究，旨在评估维利帕尼与全脑放射治疗（WBRT）联合用于脑转移瘤患者的安全性，并其次评估其抗肿瘤活性，以便为未来的试验提供依据。来自原发性实体瘤的脑转移瘤患者接受WBRT（10或15次分割，剂量为30.0或37.5 Gy）和维利帕尼（口服，剂量递增，10 - 300 mg，每日两次）治疗。评估安全性和肿瘤反应。将观察到的生存期与基于已发表的列线图预测的生存期进行比较。81例患者（中位年龄58岁）接受了治疗。最常见的原发性肿瘤类型是非小细胞肺癌（NSCLC；n = 34）和乳腺癌（n = 25）。被认为可能与维利帕尼相关的最常见不良事件（AE，≥15%）为疲劳（30%）、恶心（22%）和食欲减退（15%）。疲劳（5%）、低钾血症和低钠血症（各3%）是仅在≥2例患者中观察到的被认为可能与维利帕尼相关的3/4级不良事件。尽管这是一项非对照研究，但初步疗效结果优于预期：NSCLC亚组的中位生存时间（MST，95%CI）为10.0个月（3.9 - 13.5），乳腺癌亚组为7.7个月（2.8 - 15.0），而列线图模型预测的MST分别为3.5个月（3.3 - 3.8）和4.9个月（4.2 - 5.5）。与单独使用WBRT相比，WBRT联合维利帕尼未发现新的毒性。基于令人鼓舞的安全性和初步疗效结果，一项随机对照2b期研究正在进行中。
