Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study
Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study
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DOI：
10.1007/s11060-015-1733-1
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发表时间：
2015-04-01
影响因子：
3.9
通讯作者：
Curran, Walter J.
中科院分区：
文献类型：
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作者：
Mehta, Minesh P.;Wang, Ding;Curran, Walter J.
Veliparib是一种有效的口服PARP抑制剂，可增强放射治疗的抗肿瘤活性并穿过血脑屏障。这是一项I期剂量递增研究，评估了维利帕尼联合全脑放射治疗（WBRT）在脑转移患者中的安全性，其次是抗肿瘤活性，以便为未来的试验提供动力。患有原发性实体瘤脑转移的患者用WBRT（30.0或37.5戈伊，分10或15次）和维利帕尼（递增剂量10-300 mg，口服BID）治疗。评估安全性和肿瘤缓解。将观察到的生存率与基于已发表列线图的预测生存率进行比较。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为非小细胞肺癌（NSCLC; n = 34）和乳腺癌（n = 25）。认为可能与维利帕尼相关的最常见AE（AE，千分之一日元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%）是唯一被认为可能与维利帕尼相关的3/4级AE，在每千日元2患者中观察到。虽然这是一项非对照研究，但初步疗效结果优于预期：中位生存时间（MST，NSCLC亚组的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），而诺模图模型预测的MST为3.5个月（3.3-3.8）和4.9个月（4.2-5.5）。与单独的WBRT相比，向WBRT中添加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，一项随机对照的2b期研究正在进行中。
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, a parts per thousand yen15 %) 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 a parts per thousand yen2 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.