Ikeda Masafumi, Takahashi Hideaki, Kondo Shunsuke, Lahn Michael Mauritius Fabio, Ogasawara Ken, Benhadji Karim A, Fujii Hisaki, Ueno Hideki
National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
Cancer Chemother Pharmacol. 2017 Jun;79(6):1169-1177. doi: 10.1007/s00280-017-3313-x. Epub 2017 Apr 27.
Transforming growth factor-beta inhibitors may enhance the antitumor activity of gemcitabine with acceptable safety and tolerability. This open-label, multicenter, non-randomized phase 1b study assessed the safety/tolerability, pharmacokinetics, and tumor response of galunisertib plus gemcitabine in Japanese patients with advanced or metastatic pancreatic cancer.
During each 28-day cycle, galunisertib 150 mg was administered orally twice daily (300 mg/day) for 14 days, followed by 14 days of rest. Gemcitabine 1000 mg/m was intravenously given on Days 8, 15, and 22. Safety was assessed by the incidence of dose-limiting toxicities (DLTs) in the first cycle and treatment-emergent adverse events (TEAEs). Efficacy was assessed by antitumor activity and changes in carbohydrate antigen 19-9 (CA19-9).
No DLTs were reported. All 7 enrolled patients had ≥1 TEAE, of which the most common included anorexia, decreased neutrophil count, and decreased white blood cell count. Grade ≥3 TEAEs were observed in 6 patients; 4 patients had Grade ≥3 TEAEs (decreased neutrophil, white blood cell, and lymphocyte count; hypophosphatemia) considered possibly related to study drug(s). The pharmacokinetic profile of galunisertib in combination with gemcitabine was similar to that previously observed for galunisertib alone. The clinical response [complete response (CR), partial response (PR), or stable disease] rate was 42.9%, and the median progression-free survival was 64 days; no CR/PR were achieved.
Galunisertib plus gemcitabine had an acceptable safety/tolerability profile with evidence of efficacy in Japanese patients with advanced or metastatic pancreatic cancer.
转化生长因子-β抑制剂可能增强吉西他滨的抗肿瘤活性，且安全性和耐受性可接受。这项开放标签、多中心、非随机的1b期研究评估了加鲁尼塞替联合吉西他滨在日本晚期或转移性胰腺癌患者中的安全性/耐受性、药代动力学和肿瘤反应。
在每个28天周期中，加鲁尼塞替150毫克每日口服两次（300毫克/天），共14天，随后休息14天。吉西他滨1000毫克/平方米在第8、15和22天静脉给药。通过第一个周期中的剂量限制性毒性（DLT）发生率和治疗期间出现的不良事件（TEAE）评估安全性。通过抗肿瘤活性和糖类抗原19-9（CA19-9）的变化评估疗效。
未报告DLT。所有7名入组患者均发生≥1次TEAE，其中最常见的包括厌食、中性粒细胞计数减少和白细胞计数减少。6名患者观察到≥3级TEAE；4名患者发生≥3级TEAE（中性粒细胞、白细胞和淋巴细胞计数减少；低磷血症），被认为可能与研究药物有关。加鲁尼塞替联合吉西他滨的药代动力学特征与之前单独观察到的加鲁尼塞替相似。临床缓解率[完全缓解（CR）、部分缓解（PR）或疾病稳定]为42.9%，无进展生存期的中位数为64天；未实现CR/PR。
加鲁尼塞替联合吉西他滨具有可接受的安全性/耐受性，在日本晚期或转移性胰腺癌患者中显示出疗效证据。
