Total Neoadjuvant Therapy (TNT) for Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma

交界性可切除和局部晚期胰腺腺癌的全面新辅助治疗 (TNT)

• 批准号: 10333515
• 负责人: Alice Chia- chi Wei
• 金额: $ 64.57万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333515
• 关键词: Abdomen; Address; Adjuvant Chemotherapy; Biological; Biological Markers; Blood; Blood specimen; CA-19-9 Antigen; Cessation of life; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Trials; Computer Analysis; Correlative Study; Custom; Data; Detection; Diagnosis; Disease; Disease Management; Disease Progression; Disease-Free Survival; Distant; Distant Metastasis; Dose; Dose Fractionation; Early treatment; Evaluation; Event; Excision; Exposure to; Fluorouracil; Functional Imaging; Futile Treatments; Future; Image; Imaging Techniques; ImmunoPET; Knowledge; Lead; Leucovorin; Liposomes; Malignant neoplasm of pancreas; Measurement; Measures; Memorial Sloan-Kettering Cancer Center; Monitor; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pancreatectomy; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathologic; Patients; Phase II Clinical Trials; Prediction of Response to Therapy; Primary Neoplasm; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Recurrence; Regimen; Research; Resectable; Safety; Serum; Structure; Systemic Therapy; Time; Tissues; Translating; Treatment Protocols; Triplet Multiple Birth; Tumor Markers; Tumor Tissue; Unnecessary Surgery; X-Ray Computed Tomography; advanced pancreatic cancer; arm; base; biomarker development; blood-based biomarker; candidate marker; capecitabine; chemoradiation; chemotherapy; curative treatments; design; effective therapy; efficacy evaluation; fluorodeoxyglucose positron emission tomography; gemcitabine; human monoclonal antibodies; imaging modality; improved; improved outcome; individual patient; individualized medicine; irinotecan; liquid biopsy; novel; novel strategies; outcome prediction; oxaliplatin; patient subsets; phase II trial; phase III trial; predict clinical outcome; predicting response; predictive modeling; primary endpoint; prospective; radiomics; random forest; repository; response; response biomarker; standard care; survival prediction; targeted agent; targeted sequencing; therapy resistant; treatment effect; treatment response; treatment strategy; tumor; tumor DNA

PROJECT SUMMARY/ABSTRACT – RP1 Surgery is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC) but is available to only <20% of patients. For the 20%-30% of patients with borderline resectable or locally advanced (BR/LA; involving major abdominal vasculature) PDAC, neoadjuvant therapy with induction chemotherapy, with or without radiotherapy, is the emerging standard. This sequence with chemotherapy up-front provides the opportunity to downstage tumors to allow curative resection. Importantly, early treatment of micrometastatic disease helps select patients who are likely to benefit from surgery and spares unnecessary surgery in those who would not benefit. Evidence to date supports neoadjuvant therapy, but a more-structured, comprehensive approach is needed, which requires rigorous prospective evaluation. Moreover, there are currently no biomarkers that reliably predict treatment response or resistance. This knowledge is essential to appropriately select patients who will benefit from specific treatment regimens and to modulate treatment for individual patients. We will evaluate the efficacy of total neoadjuvant therapy (TNT) combining novel triplet chemotherapy with ablative-dose radiotherapy (AD-XRT), given before surgery, in a phase II trial (Aim 1). This trial will assess the promising 5-fluorouracil/leucovorin + liposomal-irinotecan + oxaliplatin (NALIRIFOX) regimen, administered entirely up-front for 4 months, followed by AD-XRT (biological equivalent dose of 100 Gy, delivered in 15-25 fractions, with capecitabine as radiosensitizer). The primary endpoint is event-free survival, with events defined as progression, recurrence after surgery, or death. Toward the development of biomarkers of treatment response after TNT, we will assess the potential of (Aim 2A) radiomics analysis of CT images and (Aim 2B) functional FDG-PET and novel immunoPET using 89Zr- HuMab-5B1 that recognizes cancer antigen 19-9 (CA19-9) to monitor treatment response, assess surgical resectability, and predict survival. Using blood samples collected on the trial, we will also evaluate circulating tumor DNA (measured by MSK-ACCESS targeted sequencing) and serum CA19-9 for the same purpose (Aim 3). This clinical trial aims to define TNT as a new treatment standard for BR/LA PDAC. The planned correlative studies promise to identify noninvasive biomarkers of response after TNT that may be rapidly translated to the clinic to allow adaptive disease management. As patients with BR/LA PDAC stand to benefit greatly from improvements in treatment and monitoring, because of the opportunity to enable curative resection, this project will likely have a major impact on outcomes in PDAC overall.

项目总结/摘要-RP 1 手术是胰腺导管腺癌（PDAC）患者唯一可能治愈的治疗方法， 只有<20%的患者可以使用。对于20%-30%的边缘可切除或局部晚期患者， (BR/LA;涉及主要腹部血管系统）PDAC，新辅助治疗与诱导化疗， 或不进行放射治疗，是新出现的标准。这种预先化疗的顺序提供了 有机会降低肿瘤的分期，以便进行根治性切除。重要的是，微转移的早期治疗 疾病有助于选择可能从手术中受益的患者，并在那些 谁不会受益。 迄今为止的证据支持新辅助治疗，但需要一种更结构化、更全面的方法， 这需要严格的前瞻性评估。此外，目前还没有生物标志物可以可靠地预测 治疗反应或抵抗。这些知识对于适当选择将受益的患者至关重要 从特定的治疗方案，并调整治疗个别患者。 我们将评估全新辅助治疗（TNT）联合新型三联化疗与 消融剂量放射治疗（AD-XRT），在手术前给予，在II期试验（目标1）。这次审判将评估 有前景的5-氟尿嘧啶/亚叶酸+脂质体-伊立替康+奥沙利铂（NALIFOX）方案， 完全提前4个月，然后进行AD-XRT（生物等效剂量为100戈伊，在15-25 级分，卡培他滨作为放射增敏剂）。主要终点是无事件生存期，事件定义为 进展、术后复发或死亡。 为了开发TNT后治疗反应的生物标志物，我们将评估（Aim 2A）CT图像的放射组学分析和（目的2B）功能性FDG-PET和使用89 Zr-100的新型免疫PET。 HuMab-5 B1识别癌抗原19-9（CA 19 -9），以监测治疗反应，评估手术效果， 可切除性和预测生存率。使用试验中采集的血液样本，我们还将评估循环 肿瘤DNA（通过MSK-ACCESS靶向测序测量）和血清CA 19 -9用于相同目的（Aim （3）第三章。 本临床试验旨在将TNT定义为BR/LA PDAC的新治疗标准。相关计划 研究有望确定TNT后反应的非侵入性生物标志物，这些生物标志物可以迅速转化为 诊所允许适应性疾病管理。由于BR/LA PDAC患者将从以下方面受益匪浅 治疗和监测的改善，因为有机会使根治性切除，该项目 可能会对PDAC的总体结果产生重大影响。