A phase-1 trial of intraperitoneal 5-fluorouracil and oxaliplatin in patients with colorectal cancer and unresectable peritoneal metastasis.

腹腔注射 5-氟尿嘧啶和奥沙利铂治疗结直肠癌和不可切除的腹膜转移患者的 1 期试验。

• 批准号: 10722263
• 负责人: Alex C. Kim
• 金额: $ 33.64万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722263
• 关键词: Abdomen; Address; Animal Model; Biopsy; Blood; Blood specimen; Bone Marrow; Carcinomatosis; Cell Therapy; Cells; Clinical Trials; Colorectal Cancer; Combination Drug Therapy; Combined Modality Therapy; Comprehensive Cancer Center; Disease; Dose; Effector Cell; Eligibility Determination; Flow Cytometry; Fluorouracil; Foundations; Greater sac of peritoneum; Hyperthermia; Image; Immune; Immune checkpoint inhibitor; Immunologic Stimulation; Immunooncology; Immunosuppression; Intravenous; Knowledge; Laparoscopy; Lead; Liver; Local Therapy; Lung; Malignant Neoplasms; Maximum Tolerated Dose; Methods; Minority; Modality; Modernization; Morbidity - disease rate; Myeloid Cells; Neoplasm Metastasis; Ohio; Oncology; Oncolytic viruses; Outcome; Patients; Penetration; Peritoneal; Peritoneum; Pharmacology; Phase; Phenotype; Pilot Projects; Recurrent Malignant Neoplasm; Research; Resource Sharing; Safety; Site; Systemic Therapy; Toxic effect; Tumor Debulking; Tumor Markers; Universities; Unresectable; anti-tumor immune response; antitumor agent; cancer recurrence; chemotherapy; cytotoxicity; design; early phase clinical trial; efficacy trial; gastrointestinal; immune modulating agents; immunogenic cell death; improved outcome; indexing; intraperitoneal; intraperitoneal therapy; intravenous administration; metastatic colorectal; neoplastic cell; novel; novel therapeutic intervention; oxaliplatin; patient population; peritoneal cancer; phase I trial; response; standard of care; survival outcome; systemic toxicity; tumor; tumor-immune system interactions; virtual

SUMMARY Patients with colorectal cancer (CRC) and peritoneal metastases (PM) have significantly worse outcomes than metastases to other sites like the lungs or liver. In patients with a limited volume of disease based on an intraoperatively calculated peritoneal carcinomatosis index (PCI) of less than 20, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) may provide a survival benefit. Unfortunately, only a minority of patients are candidates for CRS+HIPEC, and even in patients that undergo CRS + HIPEC, there is almost universal cancer recurrence. There is a critical need for novel therapeutic strategies, including regional delivery of anti-tumor agents in patients with CRC PM. Although 5-fluorouracil (5FU) and oxaliplatin forms the foundation of intravenous (IV) systemic therapy for patients with metastatic CRC, poor penetration and efficacy of IV chemotherapy in the peritoneum leads to much poorer outcomes. In animal models, chemotherapies such as 5FU have higher intra-tumoral concentrations and longer half-lives when administered directly to the peritoneal cavity compared to IV administration, making intraperitoneal (IP) chemotherapy an attractive treatment modality. While small pilot studies of IP 5FU from the 1980s and 90s showed promising efficacy, no systematic trials have been conducted to assess the feasibility of IP chemotherapy in patients with CRC and unresectable PM, and none using the modern chemotherapy combination of 5-FU + oxaliplatin. Furthermore, there have been no studies on the effects of IP 5FU+oxaliplatin on stimulating an anti-tumor immune response. To address these knowledge gaps, we have designed a phase-1 dose-escalation trial of 5FU and oxaliplatin administered IP in patients with CRC and PM not eligible for CRS+HIPEC due to PCI > 20. This trial will use the Bayesian optimal interval design (BOIN) to determine the maximally tolerated dose (MTD), with 6 additional patients treated at the MTD for additional safety, response, and correlative analyses. Patients will undergo a diagnostic laparoscopy with tumor biopsy at baseline and again after 4 cycles of IP chemotherapy. PCI is calculated intraoperatively at each diagnostic laparoscopy. Imaging as per SOC will be performed every 2 cycles, and response assessed by RECIST 1.1. Markers for tumor response and immune phenotype will be analyzed by spectral flow cytometry on tumor and blood samples. Our central hypothesis is that IP 5FU+oxaliplatin will be safe, lead to direct cytotoxicity, and stimulate anti-tumor immune responses due to immunogenic cell death. Additionally, local administration of chemotherapy may avoid the systemic immunosuppressive effects of systemic chemotherapy. If successful, this research will form the foundation of larger efficacy trials to optimize IP chemotherapy alone or in combination with immune-modulating agents, and ultimately, offers the potential to improve outcomes for a population of patients with poor survival, limited treatment options, and significant morbidity using affordable and widely available chemotherapy agents.

摘要 结直肠癌(CRC)和腹膜转移(PM)患者的预后明显差于 转移到其他部位，如肺或肝脏。在疾病数量有限的患者中，基于 术中计算腹膜癌指数(PCI)<20，细胞减少术(CRS) 采用高温腹膜内化疗灌流(HIPEC)可提供生存益处。不幸的是，只有 少数患者是CRS+HIPEC的候选患者，即使在接受CRS+HIPEC的患者中，也有 几乎是癌症复发的普遍现象。迫切需要新的治疗策略，包括 结直肠癌PM患者抗肿瘤药物的区域性给药 尽管5-氟尿嘧啶(5FU)和奥沙利铂构成了静脉(IV)系统治疗的基础 转移性结直肠癌患者，腹膜穿透性差和静脉化疗疗效差导致 结果要糟糕得多。在动物模型中，像5FU这样的化疗药物具有更高的肿瘤内 与静脉给药相比，直接给药时的血药浓度和半衰期更长 给药，使腹膜腔内化疗成为一种有吸引力的治疗方式。虽然是小飞行员 20世纪80年代和90年代对IP 5FU的研究显示出良好的疗效，尚未进行系统试验 对结直肠癌和不能切除的PM患者进行IP化疗的可行性评估，而没有 采用5-FU+奥沙利铂的现代化疗方案。此外，目前还没有研究 Ip 5FU+奥沙利铂刺激抗肿瘤免疫反应的研究 为了解决这些知识差距，我们设计了一项5FU和奥沙利铂的1期剂量递增试验 对因PCI&GT；20不符合CRS+HIPEC标准的结直肠癌和PM患者进行IP治疗。本试验将使用 确定最大耐受剂量(MTD)的贝叶斯最优区间设计(Boin)，另外6个 在MTD接受治疗的患者进行额外的安全性、反应性和相关性分析。患者将接受一项 诊断性腹腔镜术，肿瘤活检于基线，IP化疗4个周期后复查。PCIIS 在每次诊断性腹腔镜术中计算。按照SOC进行成像将每隔2个月执行一次 周期，以及由RECIST 1.1评估的反应。肿瘤反应和免疫表型的标志物将是 用流式细胞仪对肿瘤和血液标本进行光谱分析。我们的中心假设是IP 5FU+奥沙利铂将是安全的，导致直接的细胞毒性，并刺激抗肿瘤免疫反应 免疫原性细胞死亡。此外，局部给药可避免全身性 全身化疗的免疫抑制作用。如果成功，这项研究将为 更大的疗效试验，以优化IP化疗单独或与免疫调节剂联合使用，以及 最终，它有可能改善存活率较低、有限的患者群体的预后 使用负担得起且随处可得的化疗药物，可提供多种治疗方案和显著的发病率。