Ryan David P, Appleman Leonard J, Lynch Thomas, Supko Jeffrey G, Fidias Panagiotis, Clark Jeffrey W, Fishman Mayer, Zhu Andrew X, Enzinger Peter C, Kashala Oscar, Cusack James, Eder Joseph P
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
Cancer. 2006 Nov 15;107(10):2482-9. doi: 10.1002/cncr.22264.
Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated.
Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion) on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m(2) to 1000 mg/m(2) with bortezomib 1.0 mg/m(2) to 1.5 mg/m(2) were planned.
There were no DLTs in patients receiving bortezomib 1.0 mg/m(2) and gemcitabine 500 mg/m(2) to 1000 mg/m(2) in the first 3 dose levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2)), establishing bortezomib 1.0 mg/m(2) and gemcitabine 1000 mg/m(2) as the MTD. Most common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration.
Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.
硼替佐米是首个显示出对实体瘤有初步活性证据的蛋白酶体抑制剂。临床前研究结果促使开展一项I期试验，以确定硼替佐米与吉西他滨联合用于复发/难治性晚期实体瘤患者时的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。同时还研究了吉西他滨对硼替佐米在全血中蛋白酶体抑制作用的影响。
在21天周期的第1、4、8和11天静脉推注硼替佐米，在第1天和第8天静脉输注（30分钟）吉西他滨。每个剂量水平评估≥3例患者。计划将吉西他滨剂量从500mg/m²逐步增至1000mg/m²，硼替佐米剂量从1.0mg/m²增至1.5mg/m²。
在前3个剂量水平接受硼替佐米1.0mg/m²和吉西他滨500mg/m²至1000mg/m²的患者中未出现剂量限制性毒性。在第4剂量水平（硼替佐米1.3mg/m²，吉西他滨800mg/m²）的5例可评估患者中，有4例出现剂量限制性恶心、呕吐、胃肠道梗阻和血小板减少，确定硼替佐米1.0mg/m²和吉西他滨1000mg/m²为最大耐受剂量。最常见的≥3级毒性为中性粒细胞减少（6例患者）、血小板减少（5例患者）、胃肠道疾病（6例患者）和全身疾病（4例患者，如疲劳）。1例非小细胞肺癌患者获得部分缓解，7例病情稳定。吉西他滨联合给药不影响硼替佐米对20S蛋白酶体活性的抑制作用。
已确定适合进一步评估抗肿瘤活性的硼替佐米和吉西他滨剂量。
