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

描述(由申请人提供)： 2012年，美国估计有43920例新的胰腺癌病例。发病率几乎等同于这种致命疾病的患病率。大多数患者都患有晚期不治之症。即使采用最激进的联合化疗，转移性胰腺癌患者的中位生存期仍不到1年。人们迫切需要替代的治疗方法。一种新的抗体药物正在开发中，这种药物可以关闭刹车(癌细胞发出的信号，以逃避免疫系统的识别)，目前已知的刹车可以抑制抗癌免疫细胞。与一些癌症不同，胰腺癌不会自然地诱导这些抗癌免疫细胞。因此，疫苗是诱导和扩大肿瘤特异性免疫细胞所必需的，很可能需要与旨在关闭这些免疫细胞的刹车的药物一起使用，以避免当这些肿瘤杀伤免疫细胞渗透到肿瘤时失活。有临床前和初步的临床数据支持免疫疗法对胰腺癌有效的概念。为了在这一进展的基础上再接再厉，使治疗更有效，这项提议将在通过预先FOLFIRINOX化疗稳定下来的转移性胰腺癌患者中测试GVAX+IPI与继续标准治疗的比较。在前期化疗后整合免疫治疗有几个好处。化疗可使肿瘤细胞易受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好方法。免疫疗法可能需要几周到几个月的时间才能奏效，因此不太可能对最初无法稳定的患者起作用。GVAX+IPI在接受大量预治疗的患者中表现出了希望，在一线化疗后立即给予可能会改善活动。这项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，未来的研究将把重点放在将治疗扩大到其他胰腺癌人群，如那些有局部和切除疾病的人。 该方案的主要临床目标是比较两个治疗组的总存活率(OS)。次要临床目标是评估治疗的安全性，特别关注免疫相关的不良事件，测量CA19-9肿瘤标记物的动力学，通过RECIST(实体肿瘤反应评估标准)和免疫相关RECIST测量无进展生存期(PFS)和客观应答率。 将进行相关的免疫分析，以确定反应的预测因素。将收集外周血淋巴细胞(PBL)和血清，以确定潜在的治疗靶点和生物标志物，并预测应答和自身免疫毒性。诱导抗原特异性T细胞对间皮素的反应和改变间皮特异性T细胞表位将与OS相关。淋巴细胞端粒长度作为反应的预测指标将得到检验。Galectin-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的血清，以确定反应或毒性的靶点和生物标志物。 将获得存档的组织和治疗前和治疗后的活组织检查，以测试应答的预测因素和联合治疗的未来靶点。下一代基因组测序将用于识别免疫反应性疾病亚型，免疫组织化学将用于表征肿瘤的性质和免疫反应亚群中的免疫渗透。此外，治疗前或治疗后样本中免疫抑制分子的上调可能会识别额外的治疗靶点。

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.