Billings Clinic, Billings, Montana 59106, USA.
J Urol. 2012 Dec;188(6):2391-7. doi: 10.1016/j.juro.2012.07.097. Epub 2012 Oct 22.
We assessed the safety, pharmacokinetics and anticancer activity of intravesical CG0070, a cancer selective, replication competent adenovirus, for the treatment of nonmuscle invasive bladder cancer.
A total of 35 patients received single or multiple (every 28 days × 3 or weekly × 6) intravesical infusions of CG0070 at 1 of 4 dose levels (1 × 10(12), 3 × 10(12), 1 × 10(13) or 3 × 10(13) viral particles). Response to treatment was based on cystoscopic assessment and biopsy or urine cytology. Urine and plasma CG0070, and granulocyte-monocyte colony-stimulating factor were measured in all patients. A subset of 18 patients was assessed for retinoblastoma phosphorylation status.
Grade 1-2 bladder toxicities were the most common adverse events observed. A maximum tolerated dose was not reached. High levels of granulocyte-monocyte colony-stimulating factor were detected in urine after administration in all patients. Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3% of tested patients (7 of 12). The complete response rate and median duration of the complete response across cohorts was 48.6% and 10.4 months, respectively. In the multidose cohorts the complete response rate for the combined groups (every 28 days and weekly × 6) was 63.6% (14 of 22 patients). In an exploratory, retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8% complete response rate (9 of 11).
Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity. Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested.
我们评估了 CG0070（一种癌症选择性、复制型腺病毒）经膀胱给药治疗非肌肉浸润性膀胱癌的安全性、药代动力学和抗癌活性。
35 名患者接受了 1 种或多种剂量（4 种剂量水平中的 1 种：1×10(12)、3×10(12)、1×10(13)或 3×10(13)病毒颗粒）的 CG0070 单次或多次（每 28 天×3 次或每周×6 次）经膀胱内灌注。治疗反应基于膀胱镜评估和活检或尿细胞学。所有患者均检测了尿液和血浆中的 CG0070 及其粒细胞-单核细胞集落刺激因子。18 名患者的一部分被评估了视网膜母细胞瘤磷酸化状态。
最常见的不良反应是 1-2 级膀胱毒性。未达到最大耐受剂量。所有患者在给药后尿液中均检测到高水平的粒细胞-单核细胞集落刺激因子。在 58.3%（12 例中的 7 例）的患者中，通过尿液 CG0070 基因组在第 2 天和第 5 天之间的增加提示病毒复制。多剂量组中，联合组（每 28 天和每周×6 次）的完全缓解率和完全缓解的中位持续时间分别为 48.6%和 10.4 个月。在探索性回顾性评估中，接受多剂量方案的边缘或高视网膜母细胞瘤磷酸化患者的完全缓解率为 81.8%（11 例中的 9 例）。
经膀胱 CG0070 与可耐受的安全性和抗膀胱癌活性相关。粒细胞-单核细胞集落刺激因子转基因表达和 CG0070 复制也被提示。
