Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER).
Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER).
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DOI：
10.1016/s0140-6736(12)62166-7
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发表时间：
2013-05-25
期刊：
影响因子：
168.9
通讯作者：
Khachigian, Levon M.
中科院分区：
文献类型：
--
作者：
Cho, Eun-Ae;Moloney, Fergal J.;Cai, Hong;Au-Yeung, Annie;China, Carlos;Scolyer, Richard A.;Yosufi, Benafsha;Raftery, Mark J.;Deng, Jason Z.;Morton, Stephen W.;Hammond, Paula T.;Arkenau, Hendrik-Tobias;Damian, Diona L.;Francis, Douglas J.;Chesterman, Colin N.;Barnetson, Ross St C.;Halliday, Gary M.;Khachigian, Levon M.
c-Jun是一种核转录因子，在癌症中优先表达。研究药物Dz 13是一种靶向c-jun mRNA的脱氧核酶，可抑制一系列肿瘤的生长，包括小鼠模型中的基底细胞癌（BCC）。这项首次在人体试验（DISCOVER）的I期试验（ACTRN 12610000162011）的主要目的是确定Dz 13在BCC患者中的安全性和耐受性。次要目的是评估Dz 13药代动力学、单次瘤内注射后组织中蛋白质表达和细胞标志物的变化。2010年至2011年期间，从澳大利亚悉尼的皇家阿尔弗雷德王子医院招募了9例结节性BCC患者，并将其纳入3个递增剂量组，每组3例患者。每名患者接受单次瘤内注射剂量的Dz 13（10、30或100µg），并监测四周。试验中使用的最高剂量（100µg）为50µl注射制剂的溶解度上限，并且是临床前小鼠肿瘤研究中使用的最高浓度。在每次随访访视时，进行完整的体格检查、血液和尿液检查、心电图和药代动力学/药效学分析。在Dz 13注射后14天手术移除BCC，并与注射前活检进行比较。所有9名患者均完成了研究，无药物相关严重不良事件。未检测到全身Dz 13暴露。在用Dz 13治疗的所有9名参与者的BCC中，c-Jun表达减少。DNAzyme增加Caspase-3、-8、-9和p53，减少Bcl-2和MMP-9，并刺激肿瘤中的炎症和免疫细胞浸润。此外，9名患者中有5名患者的组织学肿瘤深度减少。Dz 13是安全的，耐受性良好，抑制其靶点，并且在单次瘤内注射后未显示出可检测的全身暴露。
c-Jun, a nuclear transcription factor, is preferentially expressed in cancer. The study drug Dz13, a deoxyribozyme targeting c-jun mRNA inhibits the growth of a range of tumors, including basal cell carcinoma (BCC) in murine models. The primary objectives of this first-in-class, first-in-human trial (DISCOVER) Phase I trial (ACTRN12610000162011) were to determine the safety and tolerability of Dz13 in patients with BCC. A secondary objective was to assess Dz13 pharmacokinetics, changes in protein expression and cell markers in the tissue following single intratumoral injection. Nine patients with nodular BCC were recruited from Royal Prince Alfred Hospital, Sydney, Australia between 2010 and 2011 and enrolled in three escalating dose groups of three patients. Each patient received a single intratumoral injected dose of Dz13 (10, 30 or 100µg) and was monitored over four weeks. The highest dose used in the trial (100µg), is at the upper limit of solubility of the formulation for a 50µl injection and was the highest concentration used in the preclinical mouse tumor studies . At each follow up visit, complete physical examination, blood and urine tests, electrocardiogram and pharmacokinetic/pharmacodynamic analyses were performed. BCCs were surgically removed 14 days post-Dz13 injection and compared with the pre-injection biopsy. All nine patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the BCC of all nine of nine participants treated with Dz13. The DNAzyme increased Caspase-3, -8, -9, and p53, reduced Bcl-2 and MMP-9, and stimulated inflammatory and immune cell infiltration in the tumors. Moreover, five of the nine patients had a reduction in histological tumor depth. Dz13 is safe, well tolerated, inhibits its target, and shows no detectable systemic exposure following single intratumoral injection.