National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
Pfizer R&D Japan, Shinjuku Bunka Quint Bldg. 3-22-7, Yoyogi, Shibuya-ku, Tokyo, 151-0053, Japan.
Invest New Drugs. 2021 Dec;39(6):1568-1576. doi: 10.1007/s10637-021-01120-7. Epub 2021 Jun 23.
Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies.
Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib.
Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (C and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily.
Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).
他拉唑帕尼是一种聚（ADP-核糖）聚合酶酶抑制剂。这项开放标签、非随机、1 期研究调查了他拉唑帕尼在日本局部晚期或转移性实体瘤患者中的安全性、药代动力学和初步抗肿瘤活性，无论其是否存在 DNA 损伤修复相关基因的突变，这些患者对标准疗法耐药/不适合标准疗法。
患者接受口服他拉唑帕尼，剂量为 0.75 或 1mg，每日一次，采用改良的 3+3 剂量递增方案。主要终点是他拉唑帕尼首个周期中的剂量限制性毒性。
共纳入 9 例患者（中位年龄 62.0 岁）：0.75mg 和 1.0mg 每日一次剂量水平各 3 例和 6 例。未报告剂量限制性毒性。最常见的治疗相关不良事件（≥2 例）为贫血、黏膜炎、斑丘疹皮疹、血小板计数降低、中性粒细胞计数降低和丙氨酸氨基转移酶升高。3 例患者发生≥3 级治疗相关不良事件（贫血、脑转移[各 1 例]和中性粒细胞及白细胞计数降低[同 1 例]）。2 例患者因治疗相关不良事件暂时停止治疗，1 例因中性粒细胞计数降低减少剂量（均为 1.0mg 每日一次）。单次和多次给药后他拉唑帕尼的暴露（C 和 AUC）与 1.0mg 他拉唑帕尼相比略有升高。总体疾病控制率为 44.4%，包括 2 例稳定疾病患者。他拉唑帕尼的推荐 2 期剂量确定为 1.0mg 每日一次。
单药他拉唑帕尼在日本晚期实体瘤患者中具有良好的耐受性和初步抗肿瘤活性。临床试验注册号：NCT03343054（2017 年 11 月 17 日）。
