Roswell Park Cancer Institute, Buffalo, New York; University of Colorado Cancer Center, Aurora, CO 80045,USA.
Clin Cancer Res. 2012 Apr 1;18(7):2048-55. doi: 10.1158/1078-0432.CCR-11-2813. Epub 2012 Feb 14.
Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer.
Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA).
Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m(2)): 750/600 (n = 4), 750/1,200 (n = 3), 1,000/600 (n = 3), 1,000/1,200 (n = 3), and 1,000/1,800 (n = 6 + 21). One dose-limiting toxicity (death) occurred at the highest dose level (1,000/1,800) tested. Non-dose-limiting ≥grade II/III toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade III/IV neutropenia, thrombocytopenia, and fatigue were seen in two, one, and two patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer, and Hodgkin lymphoma, including gemcitabine-pretreated PDA. The pharmacokinetic profile of rigosertib was not affected by gemcitabine.
The RPTD established in this study is rigosertib 1,800 mg/m(2) and gemcitabine 1,000 mg/m(2). This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy.
利戈塞替尼（一种双重非三磷酸腺苷竞争性 polo 样激酶 1（Plk1）和磷酸肌醇 3-激酶（PI3K）抑制剂）联合吉西他滨在临床前研究中具有协同抗肿瘤活性。本Ⅰ期研究旨在确定在癌症患者中联合使用利戈塞替尼和吉西他滨的推荐Ⅱ期剂量（RPTD）。
标准治疗失败或适合吉西他滨为基础治疗的实体瘤患者有资格入组。吉西他滨在 28 天周期的第 1、8 和 15 天给药，利戈塞替尼在第 1、4、8、11、15 和 18 天给药。在晚期胰腺导管腺癌（PDA）患者的扩展队列中进行了药代动力学研究。
40 例患者接受治疗，19 例在剂量递增阶段，21 例在扩展队列。评估的剂量水平为（吉西他滨/利戈塞替尼 mg/m²）：750/600（n=4）、750/1200（n=3）、1000/600（n=3）、1000/1200（n=3）和 1000/1800（n=6+21）。在最高剂量水平（1000/1800）出现 1 例剂量限制性毒性（死亡）。非剂量限制性≥2/3 级毒性包括中性粒细胞减少、淋巴细胞减少、血小板减少、疲劳和恶心。在扩展队列中，有 2 例、1 例和 2 例患者出现 3/4 级中性粒细胞减少、血小板减少和疲劳。在 PDA、胸腺癌和霍奇金淋巴瘤中观察到部分缓解，包括吉西他滨预处理的 PDA。利戈塞替尼的药代动力学特征不受吉西他滨影响。
本研究确定的 RPTD 为利戈塞替尼 1800mg/m²和吉西他滨 1000mg/m²。该方案耐受性良好，联合用药的毒性谱与吉西他滨单独用药的毒性谱相似。在吉西他滨为基础治疗后进展的患者中观察到抗肿瘤疗效。
