Phase II Study of Imatinib Mesylate in Patients with Inoperable Melanoma

描述（由申请人提供）： 黑色素瘤的发病率不断上升，晚期黑色素瘤缺乏有效的治疗方法， 疾病是一个重要的公共卫生问题。 最近的研究表明，与更常见的皮肤黑色素瘤亚型相比，来自手掌和脚底皮肤（肢端黑色素瘤）、粘膜和慢性日光损伤（CSD）皮肤的黑色素瘤具有独特的染色体改变模式。与发生在皮肤上而没有CSD的黑素瘤不同，这些不太常见的黑素瘤亚型的特征在于染色体4 q12基因座的拷贝数增加或扩增，伴随着固有酪氨酸激酶蛋白c-KIT的相关过表达和/或c-KIT的突变。 在这些黑色素瘤中鉴定的几种c-KIT突变中，有激活突变，在其他肿瘤类型如胃肠道间质瘤（GIST）中，这些突变与对c-KIT小分子抑制剂治疗的敏感性相关。 甲磺酸伊马替尼可能为这类黑色素瘤患者提供一种新的治疗选择。 本申请旨在检验以下假设：在c-KIT体细胞改变的肿瘤中，甲磺酸伊马替尼将达到至少30%的客观缓解率。 将采用Simon两阶段极大极小研究设计。 10%或更低的答复率将被视为没有希望，30%的答复率将被视为有希望。 第一类和第二类错误的概率都设为0.10。 在初始阶段，将入组16例患者。 如果少于2例患者达到缓解，则试验将关闭，认为甲磺酸伊马替尼在该患者人群中无效。 如果观察到2例或2例以上缓解，则将额外入组9例患者，直至共入组25例可评价患者。 如果在25例患者中观察到5例或更多缓解，则认为甲磺酸伊马替尼值得进一步检测。 如果真实响应率大于或等于30%，则该设计产生阳性结果的概率至少为90%。 患者将从3家当地研究中心入组。 将使用荧光原位杂交（FISH）和DNA测序对所有肿瘤进行筛查。 只有携带c-KIT扩增或胞膜结构域突变（GIST中与甲磺酸伊马替尼最大敏感性相关的突变位点）的肿瘤患者才有资格入选。 此外，将对每例患者的肿瘤进行相关研究，包括CD 117免疫组织化学以及比较基因组杂交（CGH），以进一步评估4 q12的扩增。 如果符合所有合格性标准，将为患者开具100 mg甲磺酸伊马替尼胶囊，并连续口服4粒胶囊，每日2次（400 mg BID）。 治疗6周后进行影像学检查。 显示缓解或疾病稳定且无进展证据的患者将继续接受每日甲磺酸伊马替尼治疗。 在毒性情况下允许降低剂量。 将按照每6周一次的计划进行成像研究。

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.