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Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC‐1 study design
Journal of Cachexia, Sarcopenia and Muscle ( IF 8.9 ) Pub Date : 2024-03-19 , DOI: 10.1002/jcsm.13435
John D. Groarke 1 , Jeffrey Crawford 2 , Susie M. Collins 3 , Shannon L. Lubaczewski 4 , Danna M. Breen 1 , Magdalena A. Harrington 5 , Ira Jacobs 6 , Ruolun Qiu 7 , James Revkin 1 , Michelle I. Rossulek 1 , Aditi R. Saxena 1
Affiliation  

BackgroundCancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF‐15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF‐15‐mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab‐mediated inactivation of circulating GDF‐15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF‐15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors.MethodsApproximately 168 adults with non‐small‐cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF‐15 concentrations will be randomized in a double‐blind, placebo‐controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12‐week treatment period. This is followed by optional open‐label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient‐reported appetite‐related symptoms assessed by Functional Assessment of Anorexia‐Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer‐Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities.PerspectiveCancer‐related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF‐15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life.Trial registrationClinicalTrials.gov ID: NCT05546476.

中文翻译:

ponsegromab 对癌症恶病质患者的疗效和安全性的 2 期研究:PROACC-1 研究设计

背景癌症恶病质是一种多因素代谢消耗综合征,其特征是厌食、涉及骨骼肌和脂肪组织的无意体重减轻、进行性功能障碍和生存率降低。对于这种严重病症的治疗策略非常有限。生长分化因子 15 (GDF-15) 是一种与癌症恶病质有关的细胞因子,可能代表癌症恶病质的生物标志物和潜在的治疗靶点。 Ponsegromab 是一种有效的选择性人源化单克隆抗体,可抑制 GDF-15 介导的信号传导。临床前和初步 1 期数据表明,ponsegromab 介导的循环 GDF-15 失活可能会改善恶病质的关键特征。这项 2 期研究的主要目的是评估 ponsegromab 对患有癌症、恶病质和 GDF-15 浓度升高的患者体重的影响。次要目标包括评估身体活动、身体功能、体动记录仪、食欲、恶心和呕吐、疲劳和安全性。探索性目标包括评估实体瘤的药代动力学、药效学、免疫原性、腰部骨骼肌指数和反应评估标准。方法约 168 名患有恶病质且 GDF-15 浓度升高的非小细胞肺癌、胰腺癌或结直肠癌成人将被随机分组​​,一项双盲、安慰剂对照研究 (NCT05546476)。符合资格标准的参与者将按 1:1:1:1 随机分配至 ponsegromab(100、200 或 400 mg)三个剂量组之一或匹配的安慰剂,每 4 周皮下注射一次,持续 12 周的初始治疗期。随后可选择开放标签治疗,每 4 周服用 400 mg ponsegromab,持续长达 1 年。主要终点是第 12 周时体重相对基线的平均变化。重复测量的混合模型,随后采用贝叶斯 E最大限度模型将用于初步分析。次要终点包括通过远程数字传感器测量的身体活动、身体功能和体动记录仪;通过厌食症-恶病质治疗子量表评分的功能评估评估患者报告的食欲相关症状;根据癌症相关恶病质症状日记中的问题评估厌食/食欲、恶心呕吐和疲劳;以及不良事件的发生率、安全性实验室测试、生命体征和心电图异常。观点癌症相关的恶病质是一个未得到满足的重大医疗需求领域。这项研究将支持 ponsegromab 作为一种新型 GDF-15 抑制剂的临床开发,它可能会改善癌症恶病质的关键病理,从而改善患者的症状、功能和生活质量。 试验注册临床试验网编号:NCT05546476。
更新日期:2024-03-19
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