Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma.
Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma.
复制标题
DOI：
10.1158/1078-0432.ccr-10-0822
复制
发表时间：
2010-08-01
期刊：
影响因子：
--
通讯作者：
Marshall JL
中科院分区：
文献类型：
--
作者：
Hwang JJ;Kuruvilla J;Mendelson D;Pishvaian MJ;Deeken JF;Siu LL;Berger MS;Viallet J;Marshall JL
进行了两项I期单药研究，以确定所有BCL-2抗凋亡蛋白的拮抗剂obatoclax的剂量和方案，用于II期试验的评估。两项研究GX 001和GX 005分别评价了每周1小时和3小时输注obatoclax的安全性和耐受性。两项研究中的合格患者均为患有实体瘤或淋巴瘤且体能状态为0-1的成人患者，标准治疗不适合这些患者。在GX 001研究中，最初使用加速剂量滴定设计，随后队列中有3 - 6例患者，水平之间的剂量增量为40%。在GX 005研究中，每个剂量水平有3 - 6例患者入组，水平之间的剂量增量为40%。35例患者入组研究GX 001（n = 8）和GX 005（n = 27）。使用1小时输注时间表观察到具有临床意义的中枢神经系统（CNS）毒性。由于这些输注CNS事件，GX 001中的obatoclax最大耐受剂量（MTD）为1.25 mg/m2。在GX 005中研究的3小时输注方案耐受性改善，obatoclax MTD为20 mg/m2。GX 005中1例复发性非霍奇金淋巴瘤患者获得2个月的部分缓解，1例复发性非霍奇金淋巴瘤患者病情稳定18个月。在相对低剂量（MTD，1.25 mg/m2）下，1小时输注时间表的obatoclax与神经精神剂量限制性毒性相关。实体瘤患者每周一次接受obatoclax 3小时静脉输注给药的耐受性更好（MTD，20 mg/m2），并观察到临床活性证据。
Two phase I, single-agent studies were conducted to determine the dose and regimen of obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of obatoclax, respectively. Eligible patients in both studies were adults with solid tumor or lymphoma and performance status 0–1 for whom standard therapies were not appropriate. In the GX001 study an accelerated dose titration design was initially used with subsequent cohorts of three to six patients with 40% dose increments between levels. In the GX005 study three to six patients entered at each dose level with 40% dose increments between levels. Thirty-five patients were enrolled in studies GX001 (n = 8) and GX005 (n = 27). Clinically significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m2 due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax MTD was 20 mg/m2. One patient in GX005 with relapsed non-Hodgkin’s lymphoma achieved partial response of 2 months’ duration, and one patient with relapsed non-Hodgkin’s lymphoma had stable disease for 18 months. The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric dose-limiting toxicities at relatively low doses (MTD, 1.25 mg/m2). The 3-hour i.v. infusion of obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m2), and evidence of clinical activity was observed.