IND 20212 (03-25-99) PHASE 2: ORBEC (ORAL BDP)-PATIENTS WITH CHRONIC GVHD

IND 20212 (03-25-99) 第 2 阶段：ORBEC（口服 BDP）-慢性 GVHD 患者

• 批准号: 8314497
• 负责人: Kevin James Horgan
• 金额: $ 15万
• 依托单位: SOLIGENIX, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314497
• 关键词: Acute; Adrenal Cortex Hormones; Adverse effects; Allogenic; Applications Grants; Beclomethasone; Biological Availability; Cancer Survivor; Chronic; Clinical; Clinical Research; Colon; Complication; Consensus; Cushingoid habitus; Data; Development; Disease; Dose; Drug Formulations; Enrollment; Enteral; Enteric-Coated Tablets; FDA approved; Feedback; Flare; Funding; Future; Glucocorticoids; Glucose Intolerance; Goals; Hematologic Neoplasms; In complete remission; Infection; Label; Life; Malignant Neoplasms; Medical; Methylprednisolone; Muscle Fatigue; Muscle Weakness; Oral; Oral Administration; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Placebo Control; Positioning Attribute; Prednisone; Prevention; Prevention therapy; Process; Protocols documentation; Quality of life; Reporting; Request for Applications; Research Design; Risk; Safety; Schedule; Signs and Symptoms; Small Business Innovation Research Grant; Small Intestines; Symptoms; System; Tablets; Therapeutic; Time; United States National Institutes of Health; base; bone; chronic graft versus host disease; demineralization; design; experience; follow-up; gastrointestinal; gastrointestinal sign; gastrointestinal symptom; graft vs host disease; hematopoietic cell transplantation; improved; mortality; novel; open label; partial response; phase 2 study; placebo controlled study; programs; research clinical testing; response; treatment duration

DESCRIPTION (provided by applicant): Graft vs. Host Disease (GVHD) is an expensive life-threatening complication following allogeneic hematopoietic cell transplantation in some patients that receive this life-saving treatment for certain cancers. The proposed open-label, multi-center, two-part Phase 2 clinical study is designed to evaluate the potential of orBec(R), a novel formulation of oral beclomethasone 17,21- dipropionate (BDP), as a treatment for chronic gastrointestinal cGVHD. OrBec(R), as developed by Soligenix, is formulated as two separate drug products for oral administration as an immediate release and delayed release tablet, each containing 1 mg of BDP, a potent, locally-acting corticosteroid originally developed primarily for the prevention and treatment of acute gastrointestinal graft versus host disease (aGVHD). The reduced systemic bioavailability of oral BDP offers a major therapeutic advantage over systemic glucocorticoids such as prednisone and methylprednisolone, which have well-recognized adverse effects (e.g., development of glucose intolerance, Cushingoid habitus, muscle weakness and fatigue, bone demineralization, and increased risks of infections). Adverse effects of systemic glucocorticoid administration can be avoided by use of topically active glucocorticoids. The protocol for this Phase 2 CLINICAL STUDY was submitted to IND 20,212 June 24, 2011. To date, no additional FDA feedback on the study design has been noted by the FDA. We will conduct this Phase 2 clinical study with the following specific goals, which form the Specific Aims of this proposal: To conduct a FDA reviewed and accepted Phase 2 clinical study: the study will be a point estimate design aimed at elucidating the dose response needed to define future placebo-controlled studies. The placebo-controlled study will be the Phase 3 clinical study that will be described in the Phase II SBIR proposal. This study will estimate the proportion of subjects who achieve a complete response (CR), partial response (PR) and overall response (OR) of GI GVHD signs and symptoms when treated with orBec(R), 2 mg four times a day (8 mg/day) for up to 16 weeks, in patients with cGVHD. The secondary objectives of this study are to determine the: i. proportion of subjects who experience a flare/worsening of GI GVHD; ii. time to flare/worsening of GI GVHD at each dose-level; iii. time to CR during the initial 16 weeks of orBec(R) treatment; and iv. time to flare/worsening of GI GVHD signs and symptoms during each of the planned orBec(R) dose reductions in Part 2 of the study. The safety objectives are to evaluate safety and tolerability of orBec(R) in subjects with cGVHD. Upon completion of the Phase 2 clinical study, Soligenix will be in a position to begin the process for a Phase 3 FDA reviewed and accepted clinical study, on the road to the first drug to be approved for treatment for cGVHD. PUBLIC HEALTH RELEVANCE: Currently there are no FDA approved therapies specifically for prevention or treatment of chronic GVHD (cGVHD). Furthermore, there are no FDA approved therapies for the prevention of the gastrointestinal manifestation of cGVHD. Off-label treatments (e.g., prednisone) are typically used; however, they can be associated with serious side effects that seriously diminish the quality of life for cancer survivors that have undergone life saving hematopoietic cell transplantation. More simply stated the underlying hematologic malignancy can be cured; however, the treatment utilized comes with its own set of negative consequences. This grant application requests funding to initiate (via a Phase 2 clinical study) the clinical evaluation of orBec(R), oral beclomethasone 17,21- dipropionate (BDP) for use in treating the gastrointestinal signs and symptoms associated with cGVHD. OrBec(R) is a two tablet system consisting of 1 delayed release and 1 immediate release tablet each containing 1mg BDP. The development of cGVHD and its GI complications significantly impacts the patient's quality of life and can in some cases be fatal. Based on previous clinical studies and the pharmacology of BDP, Soligenix and its medical advisors believe that orBec(R) has the potential to treat the GI manifestation of cGVHD, thereby improving the quality of life of cancer survivors as well as potentially impacting overall mortality. Upon completion of the proposed clinical study, Soligenix intends to evaluate the data generated with the intent of designing a placebo-controlled clinical study (e.g., Phase 3) to demonstrate both the safety and efficacy of orBec(R) for use in this indication.

描述(申请人提供)：移植物抗宿主病(GVHD)是一些接受某些癌症救命治疗的患者接受异基因造血细胞移植后的一种昂贵的危及生命的并发症。拟议的开放标签、多中心、 由两部分组成的第二阶段临床研究旨在评估口服倍氯米松17，21-二丙酸酯(BDP)的新配方orBec(R)作为治疗慢性胃肠道cGVHD的潜力。由Soligix公司开发的orBec(R)是两种单独的口服药物产品，分别作为速释和延缓释药片剂，每个产品含有1毫克BDP，这是一种最初主要用于预防和治疗急性胃肠道移植物抗宿主病(AGVHD)的有效的局部作用皮质类固醇。口服BDP的全身生物利用度降低提供了比全身糖皮质激素(如泼尼松和甲基强的松龙)更大的治疗优势，后者具有公认的副作用(例如，出现葡萄糖耐受不良、库辛戈德习惯性、肌肉无力和疲劳、骨骼脱钙，以及感染风险增加)。全身应用糖皮质激素的不良反应可以通过使用局部活性的糖皮质激素来避免。这项第二阶段临床研究的方案已于2011年6月24日提交给IND 20,212。到目前为止，FDA还没有注意到FDA对研究设计的额外反馈。我们将进行这项2期临床研究，具体目标如下：进行FDA审查和接受的2期临床研究：这项研究将是一项旨在阐明未来安慰剂对照研究所需的剂量反应的点估计设计。安慰剂对照研究将是第三阶段临床研究，将在第二阶段SBIR提案中描述。这项研究将估计慢性移植物抗宿主病患者服用orBec(R)，每天4次，每次2毫克(每天8毫克)，持续16周，对胃肠道移植物抗宿主病(GI GVHD)体征和症状达到完全缓解(CR)、部分缓解(PR)和总缓解(OR)的比例。这项研究的次要目标是确定：1.经历GI GVHD发作/恶化的受试者的比例；2.在每个剂量水平下GI GVHD的发作/恶化时间；初始阶段的CR时间 OrBec(R)治疗16周；在研究第二部分的每一次计划或Bec(R)剂量减少期间，GI GVHD体征和症状出现发作/恶化的时间。安全性目标是评估患有慢性移植物抗宿主病的受试者服用orBec(R)的安全性和耐受性。在第二阶段临床研究完成后，Soligix公司将能够开始FDA审查和接受的第三阶段临床研究，这将是第一种被批准用于治疗cGVHD的药物。 公共卫生相关性：目前还没有FDA批准的专门用于预防或治疗慢性移植物抗宿主病(CGVHD)的疗法。此外，目前还没有FDA批准的治疗方法来预防cGVHD的胃肠道表现。通常使用非标签治疗(如泼尼松)；然而，它们可能与严重的副作用有关，这些副作用严重降低了接受了挽救生命的造血细胞移植的癌症幸存者的生活质量。更简单地说，潜在的血液恶性肿瘤是可以治愈的；然而，所使用的治疗方法本身就有一系列负面后果。这项赠款申请要求提供资金，以启动(通过第二阶段临床研究)orBec(R)口服倍氯米松17，21-二丙酸酯(BDP)的临床评估，用于治疗与cGVHD相关的胃肠道症状和体征。OrBec(R)是一种两片系统，由1片延迟释放片和1片立即释放片组成，每片含有1毫克BDP。慢性移植物抗宿主病及其胃肠道并发症的发展严重影响患者的生活质量，在某些情况下可能是致命的。根据以前的临床研究和BDP的药理学，Soligix公司及其医疗顾问认为orBec(R)有潜力治疗cGVHD的胃肠道症状，从而改善癌症幸存者的生活质量，并可能影响总体死亡率。在拟议的临床研究完成后，Soligix公司打算评估产生的数据，目的是设计一项安慰剂控制的临床研究(例如，第三阶段)，以证明用于这一适应症的orBec(R)的安全性和有效性。