A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma.
A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma.
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DOI：
10.1002/cncr.24509
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发表时间：
2009-10-15
期刊：
影响因子：
6.2
通讯作者：
Tyler DS
中科院分区：
文献类型：
--
作者：
Beasley GM;McMahon N;Sanders G;Augustine CK;Selim MA;Peterson B;Norris R;Peters WP;Ross MI;Tyler DS
分离的肢体输注Melphalan是一种耐受性良好的治疗，对于过渡性肢体黑色素瘤患者，完全反应（CR）率约为30％。 ADH-1是一种环状五肽，它会破坏N-钙粘着蛋白的粘附复合物，并且在区域Melphalan治疗的临床前系统中进行系统地给予时，会表现出协同的抗肿瘤活性。进行了一项1阶段剂量升级研究，以评估全身性ADH-1与Melphalan通过孤立的肢体输注在透射性肢体内瘤患者中与Melphalan结合使用的安全性，耐受性，药代动力学和抗肿瘤活性。
3例患者的剂量升级队列分别在第1天和第8天接受1000、2000和4000 mg（10例）ADH-1的ADH-1患者，并在第1天通过分离的肢体输注在第1天静脉内接受。对预处理肿瘤进行链反应分析。使用实体瘤中的改良响应评估标准在3个月定义了响应。
16例患者没有观察到的剂量限制性毒性治疗。常见治疗相关的1级或2级毒性包括皮肤/皮肤病学（n = 14）和疼痛（n = 12）。 3级毒性包括呼吸急促（n = 1），高血压（n = 1），血清学毒性（n = 4）和1级4级肌酸磷酸激酶升高。现场反应包括8个CR，2个部分反应，1个稳定疾病和5种进行性疾病。药代动力学分析表明，每种剂量下的ADH-1浓度增加，而Melphalan药物水平的变异性最小。
通过孤立的肢体输注，在第1天和第8天的4000 mg剂量的全身性ADH-1是一种耐受性良好的新型靶向治疗方法，可用于区域晚期黑色素瘤。 CR的数量超出了预期，这表明靶向N-钙粘着蛋白可能是克服黑色素瘤化学耐药性的新策略。
Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed. Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n = 14) and pain (n = 12). Grade 3 toxicities included shortness of breath (n = 1), hypertension (n = 1), serologic toxicities (n = 4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels. Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.
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