Phase II Clinical Trial of a Granulocyte-Macrophage Colony-Stimulating Factor-Encoding, Second-Generation Oncolytic Herpesvirus in Patients With Unresectable Metastatic Melanoma
Phase II Clinical Trial of a Granulocyte-Macrophage Colony-Stimulating Factor-Encoding, Second-Generation Oncolytic Herpesvirus in Patients With Unresectable Metastatic Melanoma
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DOI：
10.1200/jco.2009.24.3675
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发表时间：
2009-12-01
影响因子：
45.3
通讯作者：
Nemunaitis, John J.
中科院分区：
文献类型：
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作者：
Senzer, Neil N.;Kaufman, Howard L.;Nemunaitis, John J.
目的转移性黑色素瘤的治疗选择有限。我们开展了这项II期试验，以评估JS1/34.5-/47-/粒细胞-巨噬细胞集落刺激因子（GM-CSF）在IIIc期和IV期疾病中的疗效。治疗包括肿瘤内注射高达4ml 106 pfu/mL的JS1/34.5-/47-/GM-CSF， 3周后每2周注射高达4ml 108 pfu/mL，共24次治疗。临床活动（通过RECIST[实体肿瘤反应评价标准]）、生存和安全性参数进行监测。结果50例患者（IIIc期10例，IVM1a期16例，IVM1b期4例，IVM1c期20例）平均接受6组注射；74%的患者之前接受过一种或多种非手术治疗活动性疾病，包括达卡巴嗪/替莫唑胺或白细胞介素-2 （IL-2）。不良反应主要局限于短暂的流感样症状。RECIST的总有效率为26%（完全缓解[CR]， n = 8；部分缓解[PR]， n = 5），注射和远处（包括内脏）病变均出现消退。92%的应答维持了7到31个月。另外10例患者病情稳定（SD）超过3个月，另外2例患者手术CR。在扩展方案中，2例患者随后在24个月时达到CR(1例先前PR， 1例先前SD)， 1例实现手术CR（先前PR）。1年总生存率为58%，24个月总生存率为52%。结论26%的缓解率，注射和非注射病变包括内脏部位的持久性，以及生存率，是全身有效性的证据。JS1/34.5-/47-/GM-CSF在转移性黑色素瘤中的有效性，再加上有限的毒性，值得进一步评估。美国食品和药物管理局批准的III期研究正在进行中。
PurposeTreatment options for metastatic melanoma are limited. We conducted this phase II trial to assess the efficacy of JS1/34.5-/47-/granulocyte-macrophage colony-stimulating factor (GM-CSF) in stages IIIc and IV disease.Patients and MethodsTreatment involved intratumoral injection of up to 4 mL of 106 pfu/mL of JS1/34.5-/47-/GM-CSF followed 3 weeks later by up to 4 mL of 108 pfu/mL every 2 weeks for up to 24 treatments. Clinical activity (by RECIST [Response Evaluation Criteria in Solid Tumors]), survival, and safety parameters were monitored.ResultsFifty patients (stages IIIc, n = 10; IVM1a, n = 16; IVM1b, n = 4; IVM1c, n = 20) received a median of six injection sets; 74% of patients had received one or more nonsurgical prior therapies for active disease, including dacarbazine/temozolomide or interleukin-2 (IL-2). Adverse effects were limited primarily to transient flu-like symptoms. The overall response rate by RECIST was 26% (complete response [CR], n = 8; partial response [PR], n = 5), and regression of both injected and distant (including visceral) lesions occurred. Ninety-two percent of the responses had been maintained for 7 to 31 months. Ten additional patients had stable disease (SD) for greater than 3 months, and two additional patients had surgical CR. On an extension protocol, two patients subsequently achieved CR by 24 months (one previously PR, one previously SD), and one achieved surgical CR (previously PR). Overall survival was 58% at 1 year and 52% at 24 months.ConclusionThe 26% response rate, with durability in both injected and uninjected lesions including visceral sites, together with the survival rates, are evidence of systemic effectiveness. This effectiveness, combined with a limited toxicity profile, warrants additional evaluation of JS1/34.5-/47-/GM-CSF in metastatic melanoma. A US Food and Drug Administration-approved phase III investigation is underway.