Assessment of Treatment with Visible Light Activated Synthetic Hypericin ointment in Mycosis Fungoides Patients.

7.项目总结/摘要 蕈样肉芽肿/皮肤T细胞淋巴瘤（MF/CTCL）是一种罕见的无痛性非霍奇金淋巴瘤， 淋巴瘤（NHL），没有已知的治愈方法，表现为皮肤斑块，斑块，肿瘤，或 红皮病具有显著的发病率和对健康相关生活质量（HR-QoL）的影响。 有效的早期治疗可改善HR-QoL，并可预防疾病进展。根据当前 根据NCCN指南，许多皮肤导向疗法（SDT）用于治疗早期 MF/CTCL包括局部用药、紫外线（UV）光疗和放射治疗。没有一 已被FDA批准用于一线治疗，大多数用于标签外。考虑到慢性、复发性 由于MF/CTCL的性质，大多数患者需要重复治疗并尝试其他治疗。 几种SDT的使用受到皮肤刺激/皮炎和长期累积毒性的限制。 鉴于此，迫切需要额外的SDT用于CTCL，副作用更少。局部 金丝桃素是非致突变的，不被全身吸收，被非致癌的可见光激活， 选择性地被皮肤中的肿瘤细胞吸收（高达10倍）并诱导线粒体凋亡。 MF/CTCL的I、II和III期临床研究已证明了安全性和疗效。最近的一 一项多中心、随机、安慰剂对照、设盲的III期研究，入组了169例患者， IA、IB或IIA期CTCL，每周两次给药治疗至少6周（周期 1）。在第1周期，116例受试者接受SGX 301治疗3处索引病灶，总体缓解率为 (ORR)与安慰剂相比，ORR为4%（n=50，p=0.04）。在第2周期，患者的ORR 接受SGX 301两个周期（12周）的患者为40%（p<0.0001，与安慰剂或6周的 治疗）。SGX 301治疗安全且耐受性良好，具有潜在的良好长期安全性 鉴于其作用方式。虽然试验显示了疗效，但给药方案不灵活， 持续时间短，而其他皮肤定向治疗的ORR峰值可能需要4-24个月， 治疗目前的提案将采用连续治疗研究SGX 301的疗效/安全性 在6个研究中心的50例患者的开放标签、多中心临床试验中，计划进行长达1年的研究。的 具体目的是：1：确定SGX 301治疗的最佳持续时间，以在早期达到最大ORR MF/CTCL患者接受长达12个月的“真实的世界”治疗计划。2：定义安全性特征 在治疗期间。3：评估SGX 301在疾病亚型和不同皮肤病变中的疗效 （贴片与斑块）。4：评估皮肤/外周血中的基因组变化（利用高通量 测序[HTS-PCR]和靶向下一代测序[NGS]）和凋亡标志物 （利用免疫组织化学）作为对SGX 301治疗的临床应答的相关性。

7. Project Summary/Abstract Mycosis Fungoides/Cutaneous T Cell Lymphoma (MF/CTCL) is a rare, indolent Non-Hodgkin's Lymphoma (NHL), without a known cure, that presents as skin patches, plaques, tumors, or erythroderma with significant morbidity and impact on health-related quality of life (HR-QoL). Effective early treatment improves HR-QoL and may prevent disease progression. As per current NCCN guidelines, many skin-directed therapies (SDTs) are used for the treatment of early stage MF/CTCL including topicals, ultraviolet (UV) phototherapy, and radiation therapy. None have been FDA-approved for first-line therapy and most are used off-label. Given the chronic, recurrent nature of MF/CTCL, most patients require repeat courses of therapy and trying other therapies. The use of several SDTs are limited by skin irritation/dermatitis and long-term cumulative toxicity. Given this, there is an urgent need for additional SDTs for CTCL with fewer side effects. Topical hypericin is non-mutagenic, not systemically absorbed, activated by noncarcinogenic visible light, selectively taken up by tumor cells in the skin (up to 10-fold) and induces mitochondrial apoptosis. Phase 1, 2 and 3 clinical studies in MF/CTCL have demonstrated safety and efficacy. A recent multicenter, randomized, placebo-controlled, blinded Phase 3 study, enrolled 169 patients with Stage IA, IB or IIA CTCL and administered treatments twice weekly for at least 6 weeks (Cycle 1). In Cycle 1, 116 subjects received SGX301 to 3 index lesions with an overall response rate (ORR) of 16% compared to placebo ORR 4% (n=50, p=0.04). In Cycle 2 the ORR in patients receiving SGX301 for both cycles (12 weeks) was 40% (p<0.0001 vs placebo or 6 weeks of treatment). SGX301 treatment is safe and well tolerated, with potential favorable long-term safety given its mode of action. Although the trial showed efficacy, the dosing regimen was inflexible and short duration vs other skin-directed therapies where peak ORR can take 4-24 months of treatment. The current proposal will study SGX301 efficacy/safety utilizing a continuous treatment schedule for up to 1 year in an open label, multicenter clinical trial of 50 patients over 6 sites. The Specific Aims are: 1: Define optimal duration of SGX301 therapy to maximal ORR in early stage MF/CTCL patients on a “real world” treatment schedule up to 12 months. 2: Define safety profile during treatment. 3: Assess efficacy of SGX301 in disease subtypes and different skin lesions (patch vs plaque). 4: Assess genomic changes in skin/peripheral blood (utilizing high throughput sequencing [HTS-PCR] and targeted next generation sequencing [NGS]) and apoptosis markers (utilizing immunohistochemistry) as correlates of clinical response to SGX301 therapy.