Phase 2 Study of Folfirinox Followed by Ipilimumab/GVAX in Pancreatic Cancer

Folfirinox 继 Ipilimumab/GVAX 治疗胰腺癌的 2 期研究

• 批准号: 8616181
• 负责人: DUNG T LE
• 金额: $ 40万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-02 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616181
• 关键词: Phase; Study; Folfirinox; Followed; Ipilimumab

DESCRIPTION (provided by applicant): In 2012, there were an estimated 43,920 new cases of pancreatic cancer in the United States. The incidence nearly equals the prevalence in this deadly disease. A majority of patients present with advanced, incurable disease. Even with the most aggressive combination chemotherapy, median survival for patients with metastatic pancreatic cancer remains less than 1 year. Alternative approaches to therapy are desperately needed. A new class of antibody drugs is being developed that turn off the brakes (signals sent out by the cancer cells to evade recognition by the immune system) that are now known to inhibit cancer fighting immune cells. Unlike some cancers, pancreatic cancer does not naturally induce these cancer fighting immune cells. Therefore, vaccines are necessary to induce and expand tumor specific immune cells and likely are needed to be given together with agents designed to turn off the brakes on these immune cells to avoid inactivation when these tumor killing immune cells infiltrate the tumor. There is preclinical and preliminary clinical data to support the concept that immunotherapy can work in pancreatic cancer. To build on this progress and make the therapy more effective, this proposal will test GVAX + IPI in patients with metastatic pancreatic cancer who have been stabilized with upfront FOLFIRINOX chemotherapy versus continuing standard therapy. Integrating immunotherapy after upfront chemotherapy has several advantages. Chemotherapy can predispose cancer cells to cell death mediated by immune cells. Furthermore, chemotherapy is still the best therapy to stabilize patients with pancreatic cancer. Immunotherapy can take weeks to months to be effective and is therefore unlikely to work in patients who cannot initially be stabilized. GVAX + IPI showed promise in heavily pre-treated patients and giving it immediately after front line chemotherapy is likely to improve activity. This proposal will provide the evidence needed to conduct the final approval trial that will bring immunotherapy to patients with metastatic pancreatic cancer. If the proposal is successful, future studies will focus on expanding treatment to other pancreatic cancer populations such as those with localized and resected disease. The primary clinical objective of the protocol is to compare the overall survival (OS) of the two treatment groups. The secondary clinical objectives are to assess the safety of the treatment with particular attention to immune related adverse events, to measure CA19-9 tumor marker kinetics, to measure progression-free survival (PFS) and objective response rate by RECIST (Response Evaluation Criteria In Solid Tumors) and immune-related RECIST. Correlative immune analyses will be conducted to identify predictors of response. Peripheral blood lymphocytes (PBL) and serum will be collected to identify potential therapeutic targets and biomarkers and predictors of response and autoimmune toxicity. Induction of antigen specific T cell responses to mesothelin and changes in the mesothelin-specific T cell epitope repertoire will be correlated with OS. Lymphocyte telomere length as a predictor of response will be tested. Induction of galectin-3 antibody responses will be correlated with response. Proteomic approaches will be used on pre and post treatment sera to identify targets and biomarkers of response or toxicity. Archived tissue and pre and post treatment biopsies will be obtained to test for predictors of response and future targets for combinatorial therapy. Next generation genome sequencing will be used to identify immune responsive disease subtypes and immunohistochemistry will be used to characterize the nature of tumors and immune infiltrates in responsive subsets. Furthermore, upregulation of immune inhibitory molecules in the pre or post treatment samples may identify additional therapeutic targets.

描述（由申请人提供）： 2012年，美国估计有43，920例胰腺癌新发病例。 发病率几乎等于这种致命疾病的流行率。 大多数患者患有晚期不治之症。 即使使用最积极的联合化疗，转移性胰腺癌患者的中位生存期仍低于1年。 迫切需要替代治疗方法。 目前正在开发一类新的抗体药物，可以关闭刹车（癌细胞发出的信号，以逃避免疫系统的识别），这种刹车现在已知可以抑制抗癌免疫细胞。 与某些癌症不同，胰腺癌不会自然诱导这些抗癌免疫细胞。 因此，疫苗对于诱导和扩增肿瘤特异性免疫细胞是必要的，并且可能需要与设计用于关闭这些免疫细胞的制动器的试剂一起给予，以避免当这些肿瘤杀伤免疫细胞浸润肿瘤时失活。有临床前和初步临床数据支持免疫疗法可以在胰腺癌中起作用的概念。 为了巩固这一进展并使治疗更有效，该提案将在转移性胰腺癌患者中测试GVAX + IPI，这些患者已通过前期FOLFIRINOX化疗与继续标准治疗稳定。 在前期化疗后整合免疫疗法有几个优点。化疗可使癌细胞易于发生由免疫细胞介导的细胞死亡。 此外，化疗仍然是稳定胰腺癌患者的最佳疗法。 免疫疗法可能需要数周到数月才能有效，因此不太可能对最初无法稳定的患者起作用。GVAX + IPI在重度预治疗患者中显示出希望，并且在一线化疗后立即给予它可能会改善活动。 该提案将提供进行最终批准试验所需的证据，该试验将为转移性胰腺癌患者带来免疫治疗。 如果该提议成功，未来的研究将集中于将治疗扩展到其他胰腺癌人群，例如患有局部和切除疾病的人群。 该方案的主要临床目的是比较两个治疗组的总生存期（OS）。 次要临床目的是评估治疗的安全性，特别关注免疫相关不良事件，测量CA 19 -9肿瘤标志物动力学，通过RECIST（实体瘤疗效评价标准）和免疫相关RECIST测量无进展生存期（PFS）和客观缓解率。 将进行相关免疫分析，以确定应答的预测因子。 将采集外周血淋巴细胞（PBL）和血清，以确定潜在的治疗靶点和生物标志物以及反应和自身免疫毒性的预测因子。 对间皮素的抗原特异性T细胞应答的诱导和间皮素特异性T细胞表位库的变化将与OS相关。将测试作为应答预测因子的淋巴细胞端粒长度。 半乳糖凝集素-3抗体应答的诱导将与应答相关。蛋白质组学方法将用于治疗前和治疗后血清，以鉴定反应或毒性的靶标和生物标志物。 将获得存档的组织和治疗前后的活检，以测试反应的预测因子和组合治疗的未来靶点。 下一代基因组测序将用于鉴定免疫应答疾病亚型，免疫组织化学将用于表征应答亚群中肿瘤和免疫浸润的性质。 此外，治疗前或治疗后样品中免疫抑制分子的上调可以鉴定另外的治疗靶标。