背景:TRC102通过结合无碱基位点并阻止AP内切核酸酶加工来抑制碱基切除修复;它增强了烷化剂的活性,包括替莫唑胺,在鼠类模型中。在已发表的异种移植研究中,TRC102增强了替莫唑胺的抗肿瘤作用,无论细胞系的遗传特征如何,例如,O6-甲基鸟嘌呤DNA甲基转移酶(MGMT),失配修复(MMR),或p53状态。
方法:我们在标准治疗进展的难治性实体瘤成年患者中,在28天周期的第1-5天进行了TRC102联合替莫唑胺口服1期试验。DNA损伤反应(DDR)γH2AX的核生物标志物的肿瘤诱导,pNBs1和Rad51在MGMT和MMR蛋白表达的背景下进行评估。
结果:纳入52例患者(37例升级,15个扩展),其中51个可评估的响应。推荐的2期剂量为125mgTRC102,150mg/m2替莫唑胺QDx5。常见的不良事件(3/4级)包括贫血(19%),淋巴细胞减少(12%),和中性粒细胞减少症(10%)。4例患者获得部分缓解(1例非小细胞肺癌,2颗粒细胞卵巢癌,和1例结肠癌)和13例患者病情稳定的最佳反应。15名扩展队列患者的回顾性分析未显示肿瘤MGMT低表达与患者反应之间的相关性,但是治疗在12例患者中有6例引起核Rad51反应。
结论:TRC102与替莫唑胺的组合具有活性,51名患者中有4名出现部分反应,51名患者中有13名出现稳定疾病,副作用是可管理的。
BACKGROUND: TRC102 inhibits base excision repair by binding abasic sites and preventing AP endonuclease processing; it potentiates the activity of alkylating agents, including temozolomide, in murine models. In published xenograft studies, TRC102 enhanced the antitumor effect of temozolomide regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA methyltransferase (MGMT), mismatch repair (MMR), or p53 status.
METHODS: We conducted a phase 1
trial of TRC102 with temozolomide given orally on days 1-5 of 28-day cycles in adult patients with refractory solid tumors that had progressed on standard therapy. Tumor induction of nuclear biomarkers of DNA damage response (DDR) γH2AX, pNBs1, and Rad51 was assessed in the context of MGMT and MMR protein expression for expansion cohort patients.
RESULTS: Fifty-two patients were enrolled (37 escalation, 15 expansion) with 51 evaluable for response. The recommended phase 2 dose was 125 mg TRC102, 150 mg/m2 temozolomide QDx5. Common adverse events (grade 3/4) included anemia (19%), lymphopenia (12%), and neutropenia (10%). Four patients achieved partial responses (1 non-small cell lung cancer, 2 granulosa cell ovarian cancer, and 1 colon cancer) and 13 patients had a best response of stable disease. Retrospective analysis of 15 expansion cohort patients did not demonstrate a correlation between low tumor MGMT expression and patient response, but treatment induced nuclear Rad51 responses in 6 of 12 patients.
CONCLUSIONS: The combination of TRC 102 with temozolomide is active, with 4 of 51 patients experiencing a partial response and 13 of 51 experiencing stable disease, and the side effect profile is manageable.