A Randomized, Phase IIB, Multicenter, Trial of Oral Azacytidine Plus Romidepsin versus Investigator's Choice in Patients with Relapse or Refractory Periperal T-cell lymphoma (PTCL).

项目摘要 建立了以CHOP为基础的方案，即目前治疗外周T细胞淋巴瘤（PTCL）的标准方案， 在侵袭性B细胞恶性肿瘤中，并外推至PTCL。因此，患有以下疾病的患者的中位生存期 PTCL只有1 - 3年，中位5年生存率只有20- 25%。发展PTCL的主要挑战- 具体处理与其稀有性和异质性有关。具体而言，所有PTCL的年度事故率 各民族平均患病率为1.3673/10万，患病率为5.30/10万。极端 世界卫生组织确认了该疾病的30种不同亚型，这一事实证实了这种疾病的异质性。很多行 现在的数据表明PTCL对表观遗传修饰剂表现出独特的脆弱性。以便识别 潜在的疾病的新标准，我们将进行一项随机，IIB期，多中心试验，口服 氮杂胞苷（AZA）加罗米地辛（ROMI）与研究者选择（IC），包括罗米地辛、贝利司他， 普拉曲沙和吉西他滨治疗复发性或难治性（R/R）PTCL患者。我们预计， 充分的数据将为关于全规模随机III期的“进行-不进行”决策提供信息。迄今为止， 药物已获得FDA加速批准用于治疗R/R PTCL。基于这些示例， 潜在的监管研究设计的逻辑如下：患者群体是“患有PTCL的患者， 接受过一次全身性治疗在所有先前的病例中研究了该患者人群， 加速批准（普拉曲沙、罗米地辛、贝利司他）。虽然术语PTCL涵盖多种T细胞免疫应答， 淋巴瘤组织学的，FDA已允许注册试验在这一类的T细胞 淋巴瘤恶性肿瘤由于罕见的疾病。我们将采用传统的进展终点 无生存期（PFS），用于R/R淋巴瘤（B-和T-淋巴瘤）新药的定期批准， 与用于加速批准的响应率或CR率形成对比。最后，控制臂是一个调查员， 选择包括本试验的适当和有临床意义的药物。最后，相关样本 将决定疾病的遗传特征如何影响临床结果 并将阐明该组合诱导的免疫学效应。我们相信这项研究将改变我们如何 思考未来的治疗模式，改善PTCL患者的预后。

Project Abstract CHOP-based regimens, the present standard of care for peripheral T-cell lymphoma (PTCL), were established in aggressive B-cell malignancies and extrapolated to the PTCL. As a result, the median survival of patients with PTCL is only 1 to 3 years, with a median 5-year survival of only 20-25%. Major challenges to develop PTCL- specific treatment relate to their rarity and heterogeneity. Specifically, the annual incident rate ratio of all PTCLs is 1.3673 per 100,000 among all races on average and their prevalence rate is 5.30 per 100,000. The extreme heterogeneity is affirmed by the fact that the WHO recognizes 30 distinct subtypes of the disease. Many lines of data now suggest that the PTCL exhibit a unique vulnerability to epigenetic modifiers. In order to identify potentially new standards for the disease, we will conduct a randomized, phase IIB, multicenter trial of Oral Azacytidine (AZA) plus Romidepsin (ROMI) versus Investigator’s Choice (IC) including romidepsin, belinostat, pralatrexate and gemcitabine in patients with Relapse or Refractory (R/R) PTCL. We anticipate generating sufficient data that will inform a ‘go-no-go’ decision regarding a full scale randomized Phase 3. To date, several agents have gained FDA accelerated approval for the treatment of R/R PTCL. Based on these examples, the logic for a potential regulatory study design is as follows: the patient population is “patients with PTCL who have received one prior systemic therapy.” This patient population was studied in all precedent examples of accelerated approvals (pralatrexate, romidepsin, belinostat). While the term PTCL encompasses multiple T-cell lymphoma histology’s, the FDA has permitted registration trials to be conducted in this category of T-cell lymphoma malignancies due to the rarity of the disease. We will adopt the traditional endpoint of progression free survival (PFS), used for regular approvals of new agents in R/R lymphomas (B- and T-lymphomas), in contrast to response rate or CR rate used for accelerated approvals. Lastly, the control arm is an investigator choice that includes appropriate and clinically meaningful drugs for this trial. Finally, the correlative samples obtained from patients on trial will determine how the genetic features of the disease influence clinical outcome and will clarify the immunologic effects induced by the combination. We believe this study will transform how we think about future treatment paradigms, and improve the outcomes of patients with PTCL.