Quinn Jennifer A, Desjardins Annick, Weingart Jon, Brem Henry, Dolan M Eileen, Delaney Shannon M, Vredenburgh James, Rich Jeremy, Friedman Allan H, Reardon David A, Sampson John H, Pegg Anthony E, Moschel Robert C, Birch Robert, McLendon Roger E, Provenzale James M, Gururangan Sridharan, Dancey Janet E, Maxwell Jill, Tourt-Uhlig Sandra, Herndon James E, Bigner Darell D, Friedman Henry S
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
J Clin Oncol. 2005 Oct 1;23(28):7178-87. doi: 10.1200/JCO.2005.06.502.
We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG.
For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined.
The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression.
This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.
我们对进展性恶性胶质瘤（MG）患者进行了一项两阶段临床试验。该试验的第一阶段旨在确定能有效使肿瘤AGT活性完全耗竭48小时的O6 - BG剂量。试验的第二阶段旨在确定与O6 - BG联合使用时单剂量替莫唑胺的最大耐受剂量（MTD）。此外，在给予O6 - BG后评估其血浆浓度以及O6 - 苄基 - 8 - 氧鸟嘌呤的血浆浓度。
在我们临床试验的第一阶段，患者在接受120 mg/m²的O6 - BG静脉推注1小时，随后以30 mg/m²/d的初始剂量持续输注48小时后，计划进行开颅手术以测定AGT。O6 - BG持续输注的剂量逐步增加，直至肿瘤AGT耗竭。一旦确定了O6 - BG剂量，另一组患者被纳入临床试验的第二阶段，在该阶段，在1小时的O6 - BG输注结束时给予单剂量替莫唑胺，其剂量逐步增加，直至确定MTD。
发现能有效使肿瘤AGT活性在48小时耗竭的O6 - BG剂量为静脉推注120 mg/m²超过1小时，随后以30 mg/m²/d持续输注48小时。在纳入38例处于六个替莫唑胺剂量水平的患者后，确定MTD为472 mg/m²，剂量限制性毒性仅限于骨髓抑制。
本研究为O6 - BG加替莫唑胺治疗替莫唑胺耐药的MG的II期试验奠定了基础。
