University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Gynecol Oncol. 2018 Mar;148(3):507-514. doi: 10.1016/j.ygyno.2017.12.029. Epub 2018 Jan 17.
Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies.
In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy. Veliparib dosing commenced twice-daily (BID) continuously on day 1 of cycle 2; granulocyte colony-stimulating factor was permitted. Dose escalation used a Bayesian continual reassessment method. Safety, tolerability, and efficacy were evaluated.
Seventy-five patients were enrolled (ovarian cancer, n=54; breast cancer, n=12). Thirty-six patients with ovarian cancer (67%) had known germline BRCA mutations. Most common treatment-related adverse events (TRAEs; ≥60%) were thrombocytopenia, neutropenia, nausea, and anemia. Most common grade 3/4 TRAEs (≥40%) were neutropenia and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia and neutropenia. The MTD/RP2D was established at veliparib 250mg with carboplatin AUC 4 plus gemcitabine 800mg/m. Responses were observed in 69% of patients with BRCA-deficient ovarian cancer (45% partial, 24% complete responses). Five patients remained on veliparib (80-310mg BID) for >34cycles.
Veliparib plus carboplatin/gemcitabine is tolerated, with a safety profile similar to carboplatin and gemcitabine alone. Combination therapy demonstrated promising preliminary antitumor activity in platinum-sensitive ovarian cancer patients with germline BRCA mutations. Trial registration ID: NCT01063816.
确定晚期卵巢癌和其他非血液恶性肿瘤患者中维利帕利联合卡铂和吉西他滨的最大耐受剂量（MTD）和推荐的 II 期剂量（RP2D）。
在这项 I 期研究中，转移性或不可切除的实体瘤患者和 ≤2 种既往化疗方案的患者接受维利帕利联合卡铂 AUC 4 于第 1 天和吉西他滨 800mg/m 于第 1 和 8 天的 21 天周期内，最多进行 10 个周期，随后进行可选的维利帕利维持治疗。维利帕利在第 2 周期的第 1 天开始每日两次（BID）连续给药；允许使用粒细胞集落刺激因子。剂量递增采用贝叶斯连续评估方法。评估安全性、耐受性和疗效。
共纳入 75 例患者（卵巢癌，n=54；乳腺癌，n=12）。36 例卵巢癌患者（67%）具有已知的种系 BRCA 突变。最常见的治疗相关不良事件（TRAEs；≥60%）为血小板减少症、中性粒细胞减少症、恶心和贫血。最常见的 3/4 级 TRAEs（≥40%）为中性粒细胞减少症和血小板减少症。剂量限制毒性为血小板减少症和中性粒细胞减少症。确定维利帕利 250mg 联合卡铂 AUC 4 加吉西他滨 800mg/m 的 MTD/RP2D。BRCA 缺陷型卵巢癌患者的缓解率为 69%（部分缓解 45%，完全缓解 24%）。5 例患者继续使用维利帕利（80-310mg BID）超过 34 个周期。
维利帕利联合卡铂/吉西他滨可耐受，安全性与卡铂和吉西他滨单独使用相似。联合治疗方案在具有种系 BRCA 突变的铂敏感卵巢癌患者中显示出有希望的初步抗肿瘤活性。试验注册 ID：NCT01063816。
