Phase II Study of Imatinib Mesylate in Patients with Inoperable Melanoma

描述(由申请人提供)： 黑色素瘤发病率上升，晚期黑色素瘤缺乏有效治疗 疾病是一个重要的公共卫生问题。最近的研究表明，起源于手掌和脚底皮肤(肢端黑色素瘤)、粘膜上的黑色素瘤和慢性日光损伤(CSD)皮肤的黑色素瘤，与更常见的发生在没有CSD皮肤的黑色素瘤亚型相比，具有独特的染色体变化模式。与发生在没有CSD的皮肤上的黑色素瘤不同，这些不太常见的黑色素瘤亚型的特征是4Q12基因座拷贝数或扩增增加，伴随着相关的驻留酪氨酸激酶蛋白c-kit的过度表达和/或c-kit的突变。在这些黑色素瘤中发现的几个c-kit突变中，有一些是激活突变，在其他类型的肿瘤中，如胃肠道间质瘤(GIST)，与小分子c-kit抑制剂治疗的敏感性有关。甲磺酸伊马替尼可能会为这类特殊的黑色素瘤患者提供一种新的治疗选择。这项申请建议测试假设，在c-kit发生躯体变化的肿瘤中，甲磺酸伊马替尼将达到至少30%的客观应答率。将采用西蒙两阶段极大极小研究设计。10%或更低的应答率将不被认为是有希望的，30%的应答率将被认为是有希望的。类型I和类型II错误的概率都被设置为0.10。在最初阶段，将招募16名患者。如果少于2名患者有反应，试验将结束，甲磺酸伊马替尼被认为在该患者群体中无效。如果观察到2个或更多的反应，将增加9名患者，直到总共25名可评估的患者被评估为止。如果在25名患者中观察到5个或更多的反应，那么甲磺酸伊马替尼将被认为值得进一步测试。如果真实响应率大于或等于30%，此设计将产生至少90%的肯定结果。患者将从当地3个地点招募。所有肿瘤将通过荧光原位杂交(FISH)和DNA测序进行筛查。只有携带c-kit扩增或膜旁结构域突变(GIST中与甲磺酸伊马替尼敏感性最高的突变部位)的肿瘤患者才符合条件。此外，还将对每个患者的肿瘤进行相关研究，包括CD117的免疫组织化学以及比较基因组杂交(CGH)，以进一步评估第四季度的扩增情况。如果符合所有的资格标准，患者将被开出100毫克的甲磺酸伊马替尼胶囊，并将连续口服4粒胶囊，每天两次(400毫克，每天2次)。治疗6周后将进行影像检查。有反应或病情稳定且没有进展迹象的患者将继续接受每日甲磺酸伊马替尼治疗。在毒性设置中允许减少剂量。影像检查将每6周进行一次。

DESCRIPTION (provided by applicant): The rising incidence of melanoma and the lack of effective treatments for advanced disease represents an important public health problem. Recent studies have demonstrated that melanomas arising from skin on the palms and soles (acral melanomas), on mucosal membranes, and from skin with chronic sun-induced damage (CSD) have distinctive patterns of chromosomal alterations as compared with the more common subtypes of melanoma arising on skin without CSD. Unlike melanoma occurring on skin without CSD, these less common subtypes of melanoma are characterized by increased copy numbers or amplifications of the chromosome 4q12 locus, with an associated overexpression of the resident tyrosine kinase protein c-KIT and/or mutations of c-KIT. Among the several mutations of c-KIT identified in these melanomas are the activating mutations that, in other tumor types such as gastrointestinal stromal tumors (GIST), have been associated with sensitivity to treatment with small molecule inhibitors of c-KIT. Imatinib mesylate may offer this particular subset of melanoma patients a new therapeutic option. This application proposes to test the hypothesis that, in tumors with somatic alterations of c-KIT, imatinib mesylate will achieve an objective response rate of at least 30 percent. A Simon two-stage minimax study design will be utilized. A response rate of 10 percent or less will not be considered promising, and a 30 percent response rate will be considered promising. The probabilities of a type I and type II error are both set at 0.10. In the initial stage, 16 patients will be enrolled. If fewer than 2 patients achieve a response, the trial will be closed and imatinib mesylate deemed ineffective in this patient population. If 2 or more responses are observed, 9 additional patients will be accrued until a total of 25 evaluable patients have been accrued. If 5 or more responses are observed in the 25 patients, then imatinib mesylate will be considered worthy of further testing. This design yields at least a 90 percent probability of a positive result if the true response rate is greater than or equal to 30 percent. Patients will be enrolled from 3 local sites. All tumors will be screened using florescence in-situ hybridization (FISH) and DNA sequencing. Only patients with tumors harboring c-KIT amplifications or juxtamembrane domain mutations (the mutation site associated with the greatest sensitivity to imatinib mesylate in GIST) will be eligible. In addition, correlative studies will be performed on each patient's tumor including immunohistochemistry for CD117 as well as comparative genomic hybridization (CGH) to further assess for amplification at 4q12. If all eligibility criteria are met, patients will be prescribed 100 milligrams of imatinib mesylate capsules and will take 4 capsules twice a day (400 mg BID) by mouth on a continual basis. Imaging studies will be performed after 6 weeks of therapy. Patients who show a response or stable disease and have no evidence of progression will continue receiving daily imatinib mesylate. Dose reductions are allowed in the setting of toxicity. Imaging studies will be performed on an every 6 week schedule.