A Phase II Pivotal Trial to Evaluate the Safety and Efficacy of Notrogen Mustard

描述(由申请人提供)： 这项申请是FDA-OPD赠款的第四年续展，该赠款目前为第二阶段的关键试验提供资金，测试局部氮芥末(NM)制剂在真菌样肉芽肿(MF)患者中的安全性和有效性(NCT00168064)。多发性骨髓瘤是最常见的皮肤T细胞淋巴瘤，每年约有1700例新发病例，在美国的患病率估计为16-20,000例。NM是一种烷化剂，用于淋巴瘤的全身治疗。已经证明，在0.02-0.04%的浓度范围内，NM与凡士林或Aquaffor(R)混合使用是一种安全有效的局部治疗MF的方法；特别是当最初的低浓度滴定到较高浓度的临床反应时。尽管有这种临床经验，但没有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多种浓度的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。 一种含有丙二醇(PG)的软膏配方已经被开发出来，作为重型Aquaphor(R)(AP)载体的替代品，这种载体很难涂抹在皮肤上，可能会影响患者的依从性。已经启动了一项多中心、随机、观察者盲试验，以测试生产的0.02%NM PG软膏与0.02%NM AP软膏的安全性和有效性。FDA-OPD为两个领先网站(福克斯大通癌症中心和斯坦福大学)以及行业合作伙伴和赞助商(Yaupon Treateutics，Inc.，Radnor，宾夕法尼亚州)提供资金。正在为另外11个地点提供资金。最初的应计目标为118人，现已增至200人，以适应12个月治疗期之前的撤出。现在预计应计制将在第三年完成，但分摊将持续到第四年，并在第四年完成。确诊为Ia、Ib或IIa期MF的患者符合条件。主要和次要疗效终点分别是损害严重程度指数综合评估(CAILS)和严重程度加权评估工具(SWAT)。患者每天一次将研究软膏涂抹在受影响的皮肤区域(皮损)或整个皮肤表面(取决于阶段)，持续时间长达12个月。使用频率可以根据毒性进行调整。从1-6个月开始每4周评估一次肿瘤反应和毒性，从7-12个月开始每8周评估一次。额外的毒性数据(鳞状细胞癌)将在延长的12个月的随访中获得。 Yaupon治疗公司已经为这项研究获得了FDA审查部门的特殊方案评估(SPA)和快速通道状态。

DESCRIPTION (provided by applicant): This application is a 4th year renewal of a FDA-OPD grant, that currently provides funding for a Phase 2, pivotal trial testing the safety and efficacy of topical nitrogen mustard (NM) formulations in patients with mycosis fungoides (MF)(NCT00168064). MF is the most common type of cutaneous T-cell lymphoma with an incidence of about 1,700 new cases annually and prevalence estimated at 16-20,000 cases in the USA. NM (mechlorethamine hydrochloride) is an alkylating agent, used in the systemic treatment of lymphomas. NM compounded into petrolatum or Aquaphor(r) has been shown to be a safe and effective topical treatment of MF in a 0.02-0.04% concentration range; particularly when initial lower concentrations are titrated up to clinical responses at higher concentrations. Despite this clinical experience, 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 available in multiple concentrations would be of benefit by offering a GMP product that would be available through all retail pharmacies. A propylene glycol (PG)-containing ointment formulation has been developed as an alternative to the heavy Aquaphor(r) (AP) vehicle which can be difficult to apply to the skin and can compromise patient compliance. A multi-center, randomized, observer-blind trial has been initiated to test the safety and efficacy of a manufactured 0.02% NM PG ointment versus a compounded 0.02% NM AP ointment. FDA-OPD is funding the two lead sites (Fox Chase Cancer Center and Stanford University) and the industry partner and sponsor (Yaupon Therapeutics, Inc., Radnor, Pa.) is funding eleven additional sites. The initial accrual target of 118 has been increased to 200 to accommodate for withdraws prior to the 12 month treatment period. It is now anticipated that accrual will be completed by year three but assessment will continue into and be completed by year four. Established patients with Stage Ia, Ib or IIa MF are eligible. Primary and secondary efficacy endpoints are the Composite Assessment of Index Lesion Severity (CAILS) and Severity Weighted Assessment Tool (SWAT), respectively. Patients apply study ointment to affected skin areas (lesions) or total skin surface (depending on stage) once daily for up to twelve months. The frequency of application can be adjusted for toxicity. Tumor response and toxicity are assessed every 4 weeks from months 1-6 and every 8 weeks from months 7-12. Additional toxicity data (squamous cell carcinoma) will be captured in an extended twelve-month follow-up. Yaupon Therapeutics, Inc. has secured a Special Protocol Assessment (SPA) and fast track status from the FDA Review Division for this study.