TOPICAL NITROGEN MUSTARD TREATMENT OF MYCOSIS FUNGOIDES*

描述(由申请人提供)： 这是第二阶段的修正应用，关键试验测试局部氮芥末在MF患者中的安全性和有效性。MF是最常见的皮肤T细胞淋巴瘤，每年约有1000例新发病例，在美国的患病率估计为16-20,000例。盐酸甲氯乙胺，俗称氮芥(NM)，是一种烷化剂，用于淋巴瘤的全身治疗。20世纪50年代末，首次报道了它作为局部药物治疗MF的成功。从那时起，多名研究人员已经证明了局部应用NM治疗MF的安全性和有效性。然而，到目前为止，还没有FDA批准的局部配方。因此，在非GMP环境中，这一小患者群体依赖于可用的复合药剂师。FDA批准的NM局部配方将是有益的，因为它提供了一种GMP产品，可以在所有零售药店获得。 这是一项多中心、随机、双盲、安慰剂对照研究，研究对象为既往治疗过的I期或II期MF患者。以前的治疗方法可能包括局部治疗，但不包括局部NM或局部卡莫司汀(BCNU)。严重程度加权评估工具(SWAT)将在基线(第1天)、整个12个月的研究期间和随访时完成，这是对总体表面积百分比的确定，如果有的话，还将评估临床异常淋巴结(直径1厘米)。从第1个月到第6个月每4周评估一次肿瘤反应和毒性，从第7个月到第12个月每8周评估一次。在延长的12个月的随访中将获得额外的毒性数据。其中一个病变将在治疗前、治疗中和治疗后进行活组织检查。将进行生活质量问卷调查。 共有88名患者将被纳入并随机进行治疗。患者开始治疗时，将15 mg%的NM软膏涂抹在受影响的皮肤区域(皮损)上，每天一次，持续12个月。在三个月内没有得到部分缓解(50%改善)的患者，将被升级到每天使用30 mg%的NM软膏。使用频率可以根据毒性进行调整。进展性疾病(恶化25%)或过敏性接触过敏和3/4级皮肤刺激的患者将被撤回并纳入最终反应评估。 IND参照权将由Yaupon Treateutics，Inc.提供给fccc。 这项提案的公共卫生影响将是，它将导致FDA的批准，并获得有效和安全的局部治疗(NM药膏)，用于孤儿疾病MF。

DESCRIPTION (provided by applicant): This is an amended application of a Phase 2, pivotal trial testing the safety and efficacy of topical nitrogen mustard in patients with MF. MF is the most common type of cutaneous T-cell lymphoma with an incidence of about 1,000 new cases annually and prevalence estimated at 16 to 20,000 cases in the United States. Mechlorethamine hydrochloride, commonly known as nitrogen mustard (NM), is an alkylating agent, used in the systemic treatment of lymphomas. Its successful use as a topical agent for treating MF was first reported in the late 1950s. Since then, multiple investigators have demonstrated the safety and efficacy of topically applied NM in MF. Yet, to date there are no FDA approved topical formulations. Therefore, this small patient population relies on compounding pharmacists, where available, in non-GMP environments. An FDA approved topical formulation of NM would be of benefit by offering a GMP product that would be available through all retail pharmacies. This is a multi-center, randomized, double-blind, placebo-controlled study of patients with previously treated Stage I or II MF. Prior treatments may include topical therapies, but not topical NM, or topical carmustine (BCNU). A Severity Weighted Assessment Tool (SWAT), a determination of the percentage involvement of total body surface area, and, if present, assessment of clinically abnormal lymph nodes (>1 cm diameter) will be completed at baseline (Day 1) and throughout the twelve-month study and at follow-up. Tumor response and toxicity be assessed every 4 weeks from months 1 to 6 and every 8 weeks from months 7 to 12. Additional toxicity data will be captured in an extended twelve-month follow-up. One lesion will be biopsied pre-, during, and post-treatment. Quality-of-life questionnaires will be administered. A total of 88 patients will be enrolled and randomized with intent to treat. Patients will begin treatment with l5mg% NM ointment applied to affected skin areas (lesions) once daily for up to twelve months. Patients who do not obtain a partial response (>50% improvement) within three months, will be escalated to 30mg% NM ointment daily applications. The frequency of application may be adjusted for toxicity. Patients with progressive disease (>25% worsening) or allergic contact sensitivity and grade 3/4 dermal irritation will be withdrawn and included in the final response assessment. IND referencing rights will be provided to FCCC by Yaupon Therapeutics, Inc. The public health impact of this proposal will be that it leads to FDA approval and access to an effective and safe topical therapy (NM ointment) for patients with the orphan disease MF.