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

描述（由申请人提供）：甲氧基胺（MX, NSC-3801）是一种新型化合物，通过与DMA中的apurinic/apyrimidinic （AP）位点共价结合，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基化剂的细胞毒性。MX已被研究为AP位点的结构调节剂，在临床前模型中已被证明可以增强烷基化剂的治疗效果，如替莫唑胺（TMZ, NSC-362856），具有广泛的治疗范围。基于临床前疗效和毒性特征，建议进一步开发首个进入临床开发的BER抑制剂MX: -具体目标1，我们建议在实体瘤患者中进行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。在具体目的2中，我们建议确定MX和TMZ单独和联合给药时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：i.血液单核细胞中无尿嘧啶/无嘧啶（AP）位点的测量，与单用替莫唑胺相比，甲氧基胺和替莫唑胺联合治疗后，血液单核细胞中可检测到的无尿嘧啶/无嘧啶（AP）位点预计下降至少40%。2。通过彗星法测定血液单核细胞中DMA链断裂，甲氧基胺和替莫唑胺联合治疗后检测到的单链和双链DMA断裂预计比单独使用替莫唑胺增加两倍以上。MX的临床开发有可能通过抑制肿瘤细胞用于克服烷基化化疗药物的细胞毒性作用的DMA修复机制之一，改善烷基化化疗药物治疗各种恶性肿瘤患者的预后。

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.