Small Eric J, Carducci Michael A, Burke James M, Rodriguez Ron, Fong Lawrence, van Ummersen Lynn, Yu D C, Aimi Junko, Ando Dale, Working Peter, Kirn David, Wilding George
University of California, Comprehensive Cancer Center San Francisco, San Francisco, CA 94143, USA.
Mol Ther. 2006 Jul;14(1):107-17. doi: 10.1016/j.ymthe.2006.02.011. Epub 2006 May 9.
CG7870 is a replication-selective oncolytic adenovirus genetically engineered to replicate preferentially in prostate tissue. In a previous phase I/II clinical trial of intraprostatic delivery of CG7870 for locally recurrent prostate cancer this virus was well tolerated. In this phase I study CG7870 was administered as a single intravenous infusion in a group-sequential dose escalation design (1 x 10(10) to 6 x 10(12) viral particles (vp)) to 23 patients with hormone-refractory metastatic prostate cancer. Flulike symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common adverse events. Three therapy-related grade 3 adverse events were reported, one of which (fatigue) was serious. At doses greater than 10(12) vp all five patients experienced asymptomatic grade 1 to 2 transaminitis and/or isolated d-dimer elevations starting on day 2 through 8; dose escalation was therefore halted at 6 x 10(12) vp. All tested patients had CG7870 genomes present in the peripheral blood for at least 90 minutes after infusion; patients in the highest dose group had persistence of genomes through 29 days. A "secondary" or "delayed" peak in plasma CG7870 genome copies (defined as a >10-fold increase in CG7870 genomes from nadir concentration) suggestive of active viral replication and shedding into the bloodstream was detected in 16/23 (70%) patients. CG7870 was detected in the saliva of 3 patients, whereas all urine samples tested negative. All patients developed antibodies to CG7870. Dose-related increases in interleukins 6 and 10 (IL-6, IL-10) blood levels were detected. The peak IL-6 concentration after CG7870 treatment was associated with a transient, asymptomatic decrease in blood pressure. No partial or complete prostate-specific antigen (PSA) responses were observed; however, 5 patients had a decrease in serum PSA of 25% to 49% following a single treatment, including 3 of 8 patients at the highest dose levels.
CG7870是一种经过基因工程改造的溶瘤腺病毒，具有选择性复制能力，可优先在前列腺组织中复制。在先前一项关于CG7870经前列腺内给药治疗局部复发性前列腺癌的I/II期临床试验中，该病毒耐受性良好。在这项I期研究中，CG7870采用组序贯剂量递增设计（1×10¹⁰至6×10¹²病毒颗粒（vp））通过单次静脉输注给药，治疗23例激素难治性转移性前列腺癌患者。流感样症状（发热、疲劳、寒战、恶心和/或呕吐）是最常见的不良事件。报告了3例与治疗相关的3级不良事件，其中1例（疲劳）较为严重。在剂量大于10¹² vp时，所有5例患者在第2天至第8天开始出现无症状的1至2级转氨酶升高和/或单独的D-二聚体升高；因此，剂量递增在6×10¹² vp时停止。所有受试患者在输注后外周血中CG7870基因组至少存在90分钟；最高剂量组的患者基因组持续存在长达29天。在16/23（70%）的患者中检测到血浆CG7870基因组拷贝数出现“二次”或“延迟”峰值（定义为CG7870基因组从最低点浓度增加>10倍），提示病毒活跃复制并释放到血液中。在3例患者的唾液中检测到CG7870，而所有检测的尿液样本均为阴性。所有患者均产生了针对CG7870的抗体。检测到白细胞介素6和10（IL-6、IL-10）血液水平与剂量相关的升高。CG7870治疗后IL-6浓度峰值与血压短暂、无症状下降相关。未观察到部分或完全的前列腺特异性抗原（PSA）反应；然而，5例患者在单次治疗后血清PSA下降了25%至49%，其中最高剂量组的8例患者中有3例出现这种情况。
