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)

基本信息

批准号：
10708746
负责人：
Alice Chia- chi Wei
金额：
$ 68.31万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
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/10708746
关键词：
Abdomen Address Adjuvant Chemotherapy Biological Biological Markers Blood Blood specimen CA-19-9 Antigen Cancer Detection Cessation of life Chemotherapy-Oncologic Procedure Clinic Clinical Clinical Trials Combined Modality Therapy Computer Analysis Correlative Study Data Detection Diagnosis Disease Disease Management Disease Progression Disease-Free Survival Distant Distant Metastasis Dose Early treatment Eligibility Determination Evaluation Event Excision Exposure to Fluorouracil Fractionation Functional Imaging Futile Treatments Future Image Imaging Techniques ImmunoPET Knowledge Leucovorin Liposomes Localized Disease 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 Patient Selection 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 biomarker development biomarker identification blood-based biomarker candidate marker capecitabine chemoradiation chemotherapy curative treatments design determinants of treatment resistance 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

项目摘要

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.

项目摘要/摘要 – RP1 手术是胰腺导管腺癌 (PDAC) 患者唯一可能治愈的治疗方法，但仅适用于 <20% 的患者对于 20%-30% 的临界可切除或局部晚期患者。（BR/LA；腹部主要脉管系统）PDAC，诱导化疗新辅助治疗，或不进行放射治疗，是新兴的标准，这种先行化疗的顺序提供了。重要的是，早期治疗微转移。疾病有助于选择可能从手术中受益的患者，并避免这些患者进行不必要的手术谁不会受益。迄今为止的证据支持新辅助治疗，但需要一种更有结构、更全面的方法，此外，目前还没有可靠预测的生物标志物。这些知识对于适当选择受益的患者至关重要。制定具体的治疗方案并调整针对个别患者的治疗。我们将评估新型三联化疗与总新辅助治疗 (TNT) 相结合的疗效在一项 II 期试验（目标 1）中，在手术前进行消融剂量放射治疗 (AD-XRT)。有前景的 5-氟尿嘧啶/甲酰四氢叶酸 + 脂质体伊立替康 + 奥沙利铂 (NALIRIFOX) 方案，给予完全预先进行 4 个月，然后进行 AD-XRT（生物等效剂量 100 Gy，在 15-25 天内交付）主要终点是无事件生存期，其中事件已定义。进展、手术后复发或死亡。为了开发 TNT 后治疗反应的生物标志物，我们将评估（目标 2A) CT 图像的放射组学分析和（目标 2B）功能性 FDG-PET 和使用 89Zr- 的新型免疫 PET HuMab-5B1 可识别癌症抗原 19-9 (CA19-9)，以监测治疗反应、评估手术可切除性，并使用试验中收集的血液样本预测生存率，我们还将评估循环。肿瘤DNA（通过MSK-ACCESS靶向测序测量）和血清CA19-9用于相同目的（Aim 3）。该临床试验旨在将 TNT 定义为 BR/LA PDAC 的新治疗标准。研究有望确定 TNT 后反应的非侵入性生物标志物，这些标志物可以快速转化为诊所允许适应性疾病管理，因为 BR/LA PDAC 患者将从中受益匪浅。由于有机会实现治愈性切除，该项目改善了治疗和监测可能会对 PDAC 的整体结果产生重大影响。