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

描述(由申请人提供)：甲氧胺(MX，NSC-3801)是一种新的化合物，它通过共价结合DMA中的脱嘌呤/脱嘧啶(AP)位点来抑制碱基切除修复(BER)，BER是一种重要的DMA修复途径。BER已被证明可以降低烷基化剂的细胞毒性。MX已被研究为AP部位的结构调节剂，在临床前模型中已被证明可增强烷化剂的治疗效果，如替莫唑胺(替莫唑胺，NSC-362856)，具有广泛的治疗范围。根据临床前的疗效和毒性情况，建议进一步开发第一种进入临床开发的BER抑制剂MX：-在特定目标1中，我们建议在实体肿瘤患者中进行I期试验，以确定MX和TMZ联合使用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单独和联合给药时这两种药物的药代动力学和生物活性。建议的实验室相关研究将证明生物活性，包括：i.测量血液单个核细胞中的无嘌呤/无嘧啶(AP)部位，与单用替莫唑胺相比，甲氧胺和替莫唑胺联合治疗后，血液单个核细胞中可检测到的无嘌呤/无嘧啶(AP)部位预计至少下降40%。二、用彗星试验测定血液单个核细胞中的DNA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的临床进展有可能通过抑制肿瘤细胞用来克服烷化化疗药物细胞毒作用的DMA修复机制之一来改善接受烷化化疗药物治疗的患者的预后。

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.