PHASE 1 TRIAL--BRYOSTATIN 1 AND HIGH DOSE ARA C (HIDAC)

1 期试验——苔藓抑素 1 和高剂量 ARA C (HIDAC)

• 批准号: 2552746
• 负责人: Steven Grant
• 金额: $ 7.14万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2552746
• 关键词: antileukemic agent; bioassay; blood /lymphatic pharmacology; blood chemistry; blood disorder chemotherapy; bryostatin; chronic myelogenous leukemia; clinical research; clinical trial phase I; combination chemotherapy; cytosine arabinoside; dosage; drug administration rate /duration; drug adverse effect; drug interactions; human subject; human therapy evaluation; injection /infusion; neoplasm /cancer chemotherapy; pharmacokinetics; plasma; platelet aggregation

Bryostatin 1 is a macrocyclic lactone protein kinase C (PKC) activator that has recently undergone phase I evaluation in humans. Preclinical evidence indicates that bryostatin 1 increases the susceptibility of human leukemic cells to 1-beta-D-arabinofuranosylcytosine (ara-C)- induced apoptosis in a dose- and schedule-dependent manner, and that this phenomenon is associated with bryostatin 1-mediated :PKC down- regulation. In vivo administration of bryostatin 1 has been shown to down-regulate splenocyte PKC activity in a murine model. Moreover, in a recently completed phase Ib pharmacodynamic trial in humans, a fixed dose of bryostatin 1 (25 g/M2) administered according to three schedules was observed to induce down-regulation of peripheral blood mononuclear cell PKC activity in a subset of patients. Based upon these findings, a phase I trial has been designed and subsequently approved by CTEP in which escalating doses of bryostatin 1 will be administered before and after high-dose ara-C (HIDAC) in patients with refractory leukemia. The goals of this trial are (1) to identify the MTD of bryostatin 1 administered as a 24-hour infusion immediately before and after 4 courses of HIDAC (1.5 gM/M2 q hx4 on days 1+2 and 9+10); (2) to identify the dose-limiting toxicities of this regimen; (3) to assess the effects of bryostatin 1 on HIDAC pharmacokinetics, and (4) to determine, using a platelet aggregation-based bioassay, whether escalation of the bryostatin 1 dose will lead to detectable plasma levels. Funds are now requested for clinical and data management support for this clinical trial, as well as correlative pharmacokinetic studies. It is anticipated that this trial could serve as a prototype for future studies in which agents acting through signal transduction pathways are combined with conventional cytotoxic agents in the treatment of patients with refractory hematopoietic and other malignancies.

Bryostatin 1是大环内酯蛋白激酶C（PKC）活化剂 最近在人类中进行了I期评估。 临床前 证据表明，乳头抑素1增加了 人类白血病细胞至1-beta-d-阿拉伯呋喃糖基胞嘧啶（ARA-C） - 以剂量和时间表依赖性的方式诱导凋亡，并且 该现象与乳头蛋白1介导的乳头蛋白：pkc down-介导 - 规定。 体内给药Bryostatin 1已显示为 在鼠模型中下调脾细胞PKC活性。 而且，在 最近完成的IB阶段IB药效学试验，是固定的 根据三个 观察到时间表会引起外周血的下调 一部分患者的单核细胞PKC活性。 基于这些 调查结果，I期试验已被设计并随后批准 通过ctep，将升级的bryostatin 1的剂量。 难治性患者的高剂量ARA-C（HIDAC）之前和之后 白血病。 该试验的目标是（1）确定MTD Bryostatin 1在前24小时输注和 经过4个HIDAC（第1+2和9+10的1.5 gm/m2 Q HX4）后； （2）至 确定该方案的剂量限制性毒性； （3）评估 Bryostatin 1对HIDAC药代动力学的影响，（4）确定， 使用基于血小板聚集的生物测定，是否升级 Bryostatin 1剂量将导致可检测的血浆水平。 现在是资金 要求为此临床提供临床和数据管理支持 试验以及相关的药代动力学研究。 预计 该试验可以作为未来研究的原型 通过信号转导途径作用的试剂与 常规的细胞毒性剂在治疗患者 难治性造血和其他恶性肿瘤。