TRIALS OF CLADRIBINE PLUS OTHER AGENTS FOR PEDIATRIC AML

克拉屈滨联合其他药物治疗儿童 AML 的试验

• 批准号: 6173819
• 负责人: CLINTON F STEWART
• 金额: $ 14.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-09 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173819
• 关键词: acute myelogenous leukemia; adolescence (12-20); antileukemic agent; child (0-11); chlorodeoxyadenosine; clinical research; clinical trial phase I; combination chemotherapy; cytosine arabinoside; drug administration rate /duration; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer relapse /recurrence; pediatric neoplasm /cancer; topotecan

DESCRIPTION: (Applicant's Abstract) The optimal treatment of acute myeloid leukemia (AML) in children is not yet defined. Results of contemporary treatment regimens, including those that employ bone marrow transplantation, have shown that the long-term prognosis of children and adolescents with AML, while improving, remains poor. In studies conducted at the applicant's institution it has been shown that 2-chlorodeoxyadenosine (cladribine, 2-CDA) is effective as a single agent for inducing hematologic remissions in pediatric patients with AML. Although analysis of these studies is still in progress, the overall clinical result is that about 25% of previously untreated patients show complete hematologic remission after one course of treatment with 2-CDA alone, and about 50% after two courses. For the real potential of 2-CDA for the treatment of AML to be realized, however, it is essential that a combination of 2-CDA with another drug or drugs be discovered in which the combination has the maximum additive antileukemic effect while toxicity is held to an acceptable level. In the proposed research two combinations of 2-CDA with another therapeutic agent will be investigated. One is a study of the combination of 2-CDA with cytarabine (araC) in the therapy of previously untreated patients, and the other a Phase I study of the combination of 2-CDA with topotecan. The primary objectives of the former study are: 1) to evaluate the activity and toxicity of the combination of 2-CDA plus araC; and 2) to determine the influence of 2-CDA on cytarabine triphosphate levels. Preliminary clinical results of this study are encouraging. In regard to the second combination, studies in adults with topotecan alone suggest that this might be a suitable drug to pair with 2-CDA, and preclinical results using human myeloid cells in culture indicate additive cytotoxic effects of 2-CDA and topotecan when scheduling is appropriate. The initial clinical study with 2-CDA and topotecan will be a phase I investigation in relapsed pediatric AML patients for whom no other therapy is currently available, and the objectives will be: 1) to determine the maximum tolerated doses of 2-CDA and topotecan in combination; and 2) to determine the limiting hematologic and non-hematologic toxicity. When these objectives have been met, and particularly if clinical responses are observed, a phase II trial will be designed.

描述：（申请人摘要）儿童急性髓性白血病（AML）的最佳治疗方法尚未确定。当代治疗方案（包括采用骨髓移植的治疗方案）的结果表明，患有AML的儿童和青少年的长期预后虽然有所改善，但仍然很差。在申请人所在机构进行的研究表明，2-氯脱氧腺苷（克拉屈滨，2-CDA）作为单药可有效诱导儿童AML患者的血液学缓解。虽然这些研究的分析仍在进行中，但总体临床结果是，约25%的先前未治疗的患者在单独使用2-CDA治疗一个疗程后显示完全血液学缓解，约50%在两个疗程后显示完全血液学缓解。然而，为了实现2-CDA治疗AML的真实的潜力，必须发现2-CDA与另一种药物或多种药物的组合，其中该组合具有最大的相加抗白血病作用，同时毒性保持在可接受的水平。在拟定的研究中，将研究2-CDA与另一种治疗剂的两种组合。一项是2-CDA与阿糖胞苷（araC）联合治疗既往未治疗患者的研究，另一项是2-CDA与拓扑替康联合治疗的I期研究。前一项研究的主要目的是：1）评价2-CDA + araC联合给药的活性和毒性; 2）确定2-CDA对三磷酸阿糖胞苷水平的影响。这项研究的初步临床结果令人鼓舞。关于第二种组合，在成人中单独使用托泊替康的研究表明，这可能是与2-CDA配对的合适药物，并且使用培养中的人骨髓细胞的临床前结果表明，当时间表适当时，2-CDA和托泊替康的细胞毒性作用相加。2-CDA和托泊替康的初始临床研究将是在目前没有其他治疗方法的复发性儿科AML患者中进行的I期研究，目的是：1）确定2-CDA和托泊替康联合给药的最大耐受剂量; 2）确定限制性血液学和非血液学毒性。当达到这些目标时，特别是如果观察到临床反应，将设计II期试验。