Methoxyamine and Temozolomide: A Phase I Trial Blocking Base Excision Repair

甲氧胺和替莫唑胺：阻断碱基切除修复的 I 期试验

• 批准号: 7224323
• 负责人: STANTON L. GERSON
• 金额: $ 29.81万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224323
• 关键词: Alkylating Agents; Base Excision Repairs; Binding; Biological; Biological Assay; Biological Markers; Blood; Cells; Clinical; Comet Assay; Correlative Study; DNA Double Strand Break; DNA strand break; Development; Disease; Dose-Limiting; Drops; Drug Kinetics; Future; Glioma; Laboratories; Malignant Neoplasms; Maximum Tolerated Dose; Measurement; Mononuclear; NSC-362856; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Pre-Clinical Model; Range; Research Personnel; Site; Solid Neoplasm; Therapeutic; Toxic effect; Treatment Efficacy; base; chemotherapeutic agent; cytotoxic; cytotoxicity; improved; inhibitor/antagonist; methoxyamine; neoplastic cell; novel; pre-clinical; programs; repaired; temozolomide

DESCRIPTION (provided by applicant): Methoxyamine (MX, NSC-3801) is a novel compound that inhibits base excision repair (BER), an important DMA repair pathway, by covalently binding to apurinic/apyrimidinic (AP) sites in DMA. BER has been shown to reduce the cytotoxicity of alkylating agents. MX has been studied as a structural modulator of AP sites and in preclinical models has been shown to enhance the therapeutic efficacy of alkylating agents, such as Temozolomide (TMZ, NSC-362856), with a wide therapeutic range. Based on preclinical efficacy and toxicity profile, further development of MX, the first BER inhibitor entering clinical development, is proposed: -In specific aim 1, we propose to conduct a phase I trial in patients with solid tumors to determine the maximum tolerated doses and the dose limiting toxicities of the combination of MX and TMZ. -In specific aim 2, we propose to determine the pharmacokinetics and the biological activity of the combination of MX and TMZ when these two agents are given alone and in combination. Biological activity will be demonstrated by proposed laboratory correlative studies including: i. Measurement of apurinic/apyrimidinic (AP) sites in blood mononuclear cells, with an expected drop of at least 40% in detectable apurinic/apyrimidinic (AP) sites in blood mononuclear cells following treatment with the combination of methoxyamine and temozolomide compared to temozolomide alone. ii. Determination of the DMA strand breaks by comet assay in blood mononuclear cells, with an expected greater than two-fold increase of the detected single and double stranded DMA breaks following treatment with the combination of methoxyamine and temozolomide compared to temozolomide alone. Clinical development of MX has the potential to improve outcomes of patients treated with alkylating chemotherapeutic agents for various malignancies by inhibiting one of the mechanisms of DMA repair used by tumor cells to overcome the cytotoxic effect of alkylating chemotherapeutics.

描述（由申请人提供）：甲氧胺（MX，NSC-3801）是一种新型化合物，通过共价结合 DMA 中的无嘌呤/无嘧啶（AP）位点来抑制碱基切除修复（BER），这是一种重要的 DMA 修复途径。 BER 已被证明可以降低烷化剂的细胞毒性。 MX 已被研究作为 AP 位点的结构调节剂，并且在临床前模型中已被证明可以增强烷化剂的治疗功效，例如具有广泛治疗范围的替莫唑胺（TMZ，NSC-362856）。基于临床前疗效和毒性特征，建议进一步开发第一个进入临床开发的BER抑制剂MX： -在具体目标1中，我们建议在实体瘤患者中进行I期试验，以确定MX和TMZ组合的最大耐受剂量和剂量限制毒性。 -在具体目标 2 中，我们建议确定 MX 和 TMZ 单独和联合用药时这两种药物的药代动力学和生物活性。生物活性将通过拟议的实验室相关研究来证明，包括：血液单核细胞中无嘌呤/无嘧啶 (AP) 位点的测量，与单独使用替莫唑胺相比，甲氧胺和替莫唑胺联合治疗后，血液单核细胞中可检测到的无嘌呤/无嘧啶 (AP) 位点预计下降至少 40%。二.通过彗星试验测定血液单核细胞中的 DMA 链断裂，与单独使用替莫唑胺相比，甲氧胺和替莫唑胺联合治疗后检测到的单链和双链 DMA 断裂预计增加两倍以上。 MX 的临床开发有可能通过抑制肿瘤细胞使用的 DMA 修复机制之一来克服烷基化化疗药物的细胞毒性作用，从而改善使用烷基化化疗药物治疗各种恶性肿瘤的患者的预后。