Duke University Medical Center, Durham, NC 27710, USA.
J Clin Oncol. 2011 Mar 20;29(9):1210-5. doi: 10.1200/JCO.2010.32.1224. Epub 2011 Feb 22.
Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity.
Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one).
To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.
用美法仑（M-ILI）进行理想体重（IBW）校正的隔离肢体输注（ILI）是一种耐受良好的治疗方法，适用于有转移黑色素瘤的患者，其完全缓解率为 29%。ADH-1 是一种环状五肽，可破坏 N-钙粘蛋白粘附复合物。在临床前动物模型中，全身性 ADH-1 与局部美法仑联合使用表现出协同抗肿瘤活性，在 M-ILI 的 I 期试验中，其毒性最小。
患有美国癌症联合委员会（AJCC）第 IIIB 期或 IIIC 期肢体黑色素瘤的患者接受 4000mg ADH-1 治疗，在第 1 天和第 8 天系统给药，并根据 IBW 进行 M-ILI 校正。在治疗前肿瘤上进行药物药代动力学和 N-钙粘蛋白免疫组织化学染色。主要终点是 12 周时根据实体瘤反应评估标准（RECIST）确定的反应。
在四个机构的 15 个月内，共招募了 45 名患者。在野反应包括 17 名完全缓解（CR；38%）、10 名部分缓解（22%）、6 名稳定疾病（13%）、8 名进展性疾病（18%）和 4 名（9%）无法评估。17 例 CR 中中位在野反应持续时间为 5 个月，41 例可评估患者中中位在野进展时间为 4.6 个月（95%CI，4.0 至 7.1 个月）。在 29 个肿瘤样本中检测到 N-钙粘蛋白 20 个（69%）。4 级毒性包括肌酸磷酸激酶升高（4 例）、动脉损伤（1 例）、中性粒细胞减少症（1 例）和肺炎（1 例）。
据我们所知，这项 II 期试验是首次前瞻性多中心 ILI 试验，也是首次尝试将靶向药物纳入以增强区域化疗的抗肿瘤反应。尽管靶向 N-钙粘蛋白可能会提高黑色素瘤对化疗的敏感性，但本研究未观察到治疗反应的差异。
