Phase I/II Study of Oncolytic HSVGM-CSF in Combination with Radiotherapy and Cisplatin in Untreated Stage III/IV Squamous Cell Cancer of the Head and Neck
Phase I/II Study of Oncolytic HSVGM-CSF in Combination with Radiotherapy and Cisplatin in Untreated Stage III/IV Squamous Cell Cancer of the Head and Neck
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DOI：
10.1158/1078-0432.ccr-10-0196
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发表时间：
2010-08-01
影响因子：
11.5
通讯作者：
Nutting, Christopher M.
中科院分区：
文献类型：
--
作者：
Harrington, Kevin J.;Hingorani, Mohan;Nutting, Christopher M.
目的：本研究旨在确定 JS1/34.5-/47-/GM-CSF 的推荐剂量，JS1/34.5-/47-/GM-CSF 是一种编码人粒细胞巨噬细胞集落刺激因子 (GM-CSF) 的溶瘤单纯疱疹病毒 1 型病毒 (HSV-1)，用于头颈鳞状细胞癌 (SCCHN) 患者与放化疗联合治疗的未来研究。 实验设计：分期患者III/IVA/IVB SCCHN 接受放化疗（70 Gy/35 分次，第 1、22 和 43 天同时使用顺铂 100 mg/m(2)），并且剂量递增（队列 1 为 10(6)、10(6)、10(6)、10(6) pfu/mL；10(6)、10(7)、队列2为10(7)、10(7)；队列3为10(6)、10(8)、10(8)、10(8))在第1、22、43和64天通过瘤内注射JS1/34.5-/47-/GM-CSF。患者在6至10周后接受颈清扫术。主要终点是安全性和未来研究的推荐剂量/时间表。次要终点包括抗肿瘤活性（放射学、病理学）。还监测了复发率和生存率。结果：17 名患者接受了治疗，没有延误放化疗或剂量限制性毒性。根据实体瘤疗效评估标准，14 名患者 (82.3%) 表现出肿瘤缓解，93% 的患者在颈清扫术中得到病理完全缓解。在注射的肿瘤和邻近的未注射的肿瘤中检测到 HSV 水平高于输入剂量，表明病毒复制。所有患者在治疗结束时均为血清阳性。无患者出现局部复发，中位随访 29 个月（范围：19-40 个月）时，疾病特异性生存率为 82.4%。 结论：JS1/34.5-/47-/GM-CSF 联合顺铂放化疗对 SCCHN 患者耐受性良好。推荐的 II 期剂量为 10(6)、10(8)、10(8)、10(8)。所有患者均实现了局部控制，迄今为止无复发率为 76.5%。有必要在当地先进的 SCCHN 中进一步研究这种方法。临床癌症研究； 16（15）； 4005-15。 (C) 2010 AACR。
Purpose: This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN).Experimental Design: Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m(2) on days 1, 22, and 43) and dose-escalating (10(6), 10(6), 10(6), 10(6) pfu/mL for cohort 1; 10(6), 10(7), 10(7), 10(7) for cohort 2; 10(6), 10(8), 10(8), 10(8) for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored.Results: Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months).Conclusions: JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 10(6), 10(8), 10(8), 10(8). Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN. Clin Cancer Res; 16(15); 4005-15. (C) 2010 AACR.