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.

总结 结直肠癌（CRC）和腹膜转移（PM）患者的预后显著差于 转移到其他部位，如肺或肝。在基于一个 术中计算的腹膜癌转移指数（PCI）小于20，细胞减灭术（CRS） 与热腹腔内化疗灌注（HIPEC）可以提供生存的好处。不幸的是，只有一个 少数患者是CRS+HIPEC的候选者，即使在接受CRS + HIPEC的患者中， 几乎普遍的癌症复发。迫切需要新的治疗策略，包括 在患有CRC PM的患者中局部递送抗肿瘤剂。 虽然5-氟尿嘧啶（5 FU）和奥沙利铂形成静脉（IV）全身治疗的基础， 对于转移性CRC患者，腹膜中IV化疗的渗透性和有效性差导致 更糟糕的结果。在动物模型中，化学疗法如5 FU具有较高的肿瘤内肿瘤生长。 与IV给药相比， 因此，腹膜内（IP）化疗是一种有吸引力的治疗方式。虽然小飞行员 20世纪80年代和90年代的IP 5 FU研究显示出有希望的疗效，但尚未进行系统性试验。 评估IP化疗在CRC和不可切除PM患者中的可行性， 使用5-FU +奥沙利铂的现代化疗组合。此外，没有任何研究表明， IP 5 FU+奥沙利铂对刺激抗肿瘤免疫应答的作用。 为了解决这些知识缺口，我们设计了一项5 FU和奥沙利铂的I期剂量递增试验 在患有CRC和PM的患者中施用IP，由于PCI > 20而不适合CRS+HIPEC。这次审判将使用 贝叶斯最优区间设计（BOIN）确定最大耐受剂量（MTD），6个额外的 接受MTD治疗的患者进行额外的安全性、缓解和相关性分析。患者将接受 在基线和4个周期IP化疗后再次进行诊断性腹腔镜检查和肿瘤活检。PCI是 在每次诊断性腹腔镜检查术中计算。根据SOC，将每2次进行成像 周期，并通过RECIST 1.1评估缓解。肿瘤反应和免疫表型的标志物将在 通过光谱流式细胞术对肿瘤和血液样品进行分析。我们的核心假设是， 5 FU+奥沙利铂将是安全的，导致直接的细胞毒性，并刺激抗肿瘤免疫应答， 免疫原性细胞死亡。此外，局部施用化疗可避免全身性化疗。 全身化疗的免疫抑制作用。如果成功，这项研究将为 更大规模的疗效试验，以优化IP化疗单独或与免疫调节剂联合使用，以及 最终，提供了改善生存率低、有限的患者人群结局的潜力。 治疗选择，以及使用负担得起的和广泛可用的化疗剂的显著发病率。