Ranson Malcolm, Middleton Mark R, Bridgewater John, Lee Siow Ming, Dawson Martin, Jowle Debra, Halbert Gavin, Waller Sue, McGrath Helen, Gumbrell Lindsey, McElhinney R Stanley, Donnelly Dorothy, McMurry T Brian H, Margison Geoffrey P
Department of Medical Oncology, University of Manchester, UK.
Clin Cancer Res. 2006 Mar 1;12(5):1577-84. doi: 10.1158/1078-0432.CCR-05-2198.
A major mechanism of resistance to temozolomide involves the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase). The main aims of this phase I trial were to determine an ATase-depleting dose (ADD) of lomeguatrib, a potent pseudosubstrate inhibitor, and to define a suitable dose of temozolomide to be used in combination with lomeguatrib in patients with advanced cancer.
Lomeguatrib was administered at dose levels of 10 to 40 mg/m2 days 1 to 5, as a single agent, and also in combination with temozolomide. Once the ADD of lomeguatrib was identified, the dose of temozolomide in combination was increased, in successive patient cohorts, from 50 to 175 mg/m2 on days 1 to 5 of a 28-day cycle to define the maximal tolerated dose and dose-limiting toxicity of the combination.
Thirty-eight patients with advanced solid tumors were enrolled. More than 95% ATase depletion within 4 hours of the first dose was achieved in peripheral blood mononuclear cells at lomeguatrib doses of > or =10 mg/m2/d i.v. or > or =20 mg/m2/d orally, and tumor biopsies showed > or =92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m2 days 1 to 5. The dose limiting toxicity of the combination of lomeguatrib and temozolomide was myelosuppression. The toxicity of lomeguatrib alone was minimal. In 23 patients with measurable disease, one complete response was seen and 12 patients had stable disease for at least 3 months.
This first administration of lomeguatrib to man successfully established an oral ADD of lomeguatrib and identified a combination regimen with temozolomide suitable for future clinical evaluation.
对替莫唑胺耐药的一个主要机制涉及DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（ATase）。该I期试验的主要目的是确定洛美曲贝（一种有效的假底物抑制剂）的ATase耗竭剂量（ADD），并确定晚期癌症患者中与洛美曲贝联合使用的合适替莫唑胺剂量。
洛美曲贝在第1至5天以10至40mg/m²的剂量水平作为单一药物给药，也与替莫唑胺联合给药。一旦确定了洛美曲贝的ADD，在连续的患者队列中，联合使用的替莫唑胺剂量在28天周期的第1至5天从50mg/m²增加到175mg/m²，以确定联合用药的最大耐受剂量和剂量限制性毒性。
38例晚期实体瘤患者入组。洛美曲贝静脉注射剂量≥10mg/m²/天或口服剂量≥20mg/m²/天时，外周血单核细胞在首剂后4小时内实现了超过95%的ATase耗竭，肿瘤活检显示ATase耗竭≥92%。在洛美曲贝静脉注射的ADD剂量下，替莫唑胺联合使用的最大耐受剂量为第1至5天150mg/m²。洛美曲贝与替莫唑胺联合用药的剂量限制性毒性是骨髓抑制。单独使用洛美曲贝的毒性极小。在23例可测量疾病的患者中，观察到1例完全缓解，12例患者疾病稳定至少3个月。
洛美曲贝首次用于人体成功确定了洛美曲贝的口服ADD，并确定了一种与替莫唑胺联合的方案，适合未来的临床评估。
