Phase II Study of Imatinib Mesylate in Patients with Inoperable Melanoma

甲磺酸伊马替尼治疗不能手术的黑色素瘤患者的 II 期研究

• 批准号: 7371810
• 负责人: GARY K SCHWARTZ
• 金额: $ 26.28万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371810
• 关键词: Phase; II; Study; Imatinib; Mesylate

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.

描述（由申请人提供）： 黑色素瘤的发生率上升和缺乏高级治疗方法 疾病是一个重要的公共卫生问题。 最近的研究表明，与慢性太阳诱导损伤（CSD）的皮肤上的皮肤（杂色黑色素瘤）在皮肤上产生的黑色素瘤（Acral黑色素瘤）具有与没有CSD的皮肤上更常见的亚素瘤相比，具有独特的染色体改变模式。与没有CSD的皮肤上发生的黑色素瘤不同，这些较不常见的黑色素瘤亚型的特征是增加拷贝数或4q12染色体基因座的扩增，并与驻留的酪氨酸激酶蛋白C-kit的过度表达和/或C-KIT的突变相关。 在这些黑色素瘤中鉴定出的C-KIT的几个突变中，有激活突变，在其他肿瘤类型（例如胃肠道基质肿瘤（GIST））中，这些突变与对用小分子C-KIT抑制剂治疗的敏感性有关。 伊马替尼甲酸可能会为这一特殊的黑色素瘤患者提供新的治疗选择。 该应用建议测试以下假设：在C-KIT躯体改变的肿瘤中，伊马替尼甲酸酯将达到至少30％的客观反应率。 Simon两阶段的最小研究设计将被使用。 10％或更低的回应率将不被视为有希望的，并且30％的回应率将被视为有希望的。 I型和II型误差的概率均设置为0.10。 在最初的阶段，将入学16名患者。 如果少于2名患者得到反应，则该试验将被关闭，伊马替尼在该患者人群中认为无效。 如果观察到2个或更多反应，则有9例额外的患者将被累积，直到总共有25名可评估的患者。 如果在25名患者中观察到5个或更多反应，则伊马替尼甲酸酯将被认为值得进一步测试。 如果真实响应率大于或等于30％，则该设计至少产生90％的概率。 患者将从3个本地地点招收。 所有肿瘤将使用荧光原位杂交（FISH）和DNA测序筛选。 只有具有含有C-KIT扩增或近膜结构域突变的肿瘤患者（与GIST中对伊马替尼的敏感性最大的敏感性相关的突变位点）才有资格。 此外，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4q12的扩增。 如果满足所有资格标准，将为患者开处方100毫克的伊马替尼梅赛酸胶囊胶囊，并将每天两次（400毫克bid）持续服用4胶囊。 在治疗6周后将进行成像研究。 表现出反应或稳定疾病且没有进展证据的患者将继续接受每日伊马替尼梅赛酸盐。 在毒性的情况下允许降低剂量。 成像研究将每6周时间表进行一次。